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
Status of the Claims
1. Claims 1-47 are the original claims filed 7/5/2023. In the Preliminary Amendment of 10/26/2023, claims 1-47 are canceled and new claims 48-77 are added. Claims 48-77 are pending.
Priority
2. USAN 18/346,975, filed 07/05/2023, is a Divisional of 17/477,651, filed 09/17/2021, now U.S. Patent # 11739153 and having 1 RCE-type filing therein, claims foreign priority to JP 2020-157873, filed 09/18/2020.
Information Disclosure Statement
3. As of 1/22/2026, a total of seven (7) IDS are filed: 8/16/2023; 8/24/2023; 9/8/2023; 5/29/2024; 7/18/2024; 1/14/2025; and 9/16/2025. The corresponding initialed and dated 1449 form is considered and of record.
4. The listing of references in the specification is not a proper information disclosure statement. See [0003]. 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.
Objections
Specification
5. The abstract of the disclosure is objected to because it contains:
a) two separate paragraphs: the first repeats information given in the title (i.e., “anti-HLA-DQ2.5 antibody and its use for the treatment of celiac disease”); and the second describes the invention.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
b) a typographical error in the 1st paragraph for “its use” that should be “their use” in order to reflect the plurality of the antibodies.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
6. The disclosure is objected to because of the following informalities:
a) The use of the term BiaCore, Tween, GraphPad, BLASTX, NCBI, UNIX, MEGALIGN, DNASTAR, GenBank, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Objections
7. Claims 56-57, 65-66 and 73-74 are objected to because of the following informalities:
a) Claims 56, 65 and 73 recite what appears to be closed, Markush group-like language but is otherwise unclear, i.e., “are independently selected from the following list:” See MPEP 2117.
b) Claims 57, 66 and 74 recite what appears to be closed, Markush group-like language but is otherwise unclear, i.e., “from the group below:” See MPEP 2117.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Written Description
8. Claims 48-55, 58-64, 67-72 and 75-77 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim interpretation
The claims are drawn to any known-or-yet to be discovered gluten peptide that is antigenic and to which the bispecific antibody without expressing any degree of specificity, non-specificity and/or cross-reactivity with respect to the binding of the gluten peptides is encompassed by the claims.
Even where the claims recite “a complex of” HLA-DQ2.5 and a first/second gluten peptide, the ordinary artisan cannot envisage what the scope of a universe of gluten peptides would encompass much less the source of the gluten proteins.
See Biesiekierski (Journal of Gastroenterology and Hepatology 2017; 32 (Suppl. 1): 78–81) (IDS 8/16/2023)) stating that “gluten is a very complex compound, characterized by high allelic polymorphism encoding its specific proteins, glutenin, and gliadin. Furthermore, each wheat genotype produces unique types and quantities of these compounds, which can also differ by varied growing conditions and technological processes. The protein (and also carbohydrate) expression of one genotype can change depending on the environment where it was grown, for example, the ω-5 gliadin content increases with fertilization and temperature during maturity.” If the gluten protein composition varies as according to Biesiekierski, then the proteins and peptide derived therefrom is unpredictable in its sequence identity.
Wieser (Food Microbiology 24 (2007) 115–119) (IDS 8/16/2023)) substantiates the diversity of the gluten family of proteins stating “Gluten contains hundreds of protein components which are present either as monomers or, linked by interchain disulphide bonds, as oligo- and polymers (Wrigley and Bietz, 1988). They are unique in terms of their amino acid compositions, which are characterized by high contents of glutamine and proline and by low contents of amino acids with charged side groups.”
The ordinary artisan cannot not even readily envisage what in the universe of gluten peptides would associate in a complex formation with the HLA-DQ2.5 in order for the antibodies of the invention to bind with predictability much less specificity, non-specificity and/or cross-reactivity.
It has been well known that minor structural differences even among structurally related compounds can result in substantially different binding activities for the same antibody. Adequate written description for an antibody appears to hinge upon whether the specification provides adequate written description for the antigen. While a specification may enable making a genus of antibodies, this does not necessarily place applicant in possession of the resultant antibodies (See In re Kenneth Alonso October (Fed. Cir. 2008) sustaining a lack of adequate written description rejection where “the specification teaches nothing about the structure, epitope characterization, binding affinity, specificity, or pharmacological properties common to the large family of antibodies” where the specification does not characterize the antigens to which the monoclonal antibodies must bind).
Also see for example, Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co. (Fed. Cir. 2010) (en banc) stating:
"a few broad principles hold across all cases"; “We have made clear that the written description requirement does not demand either examples or an actual reduction to practice; a constructive reduction to practice that in a definite way identifies the claimed invention can satisfy the written description requirement. Falko-Gunter Falkner v. Inglis, 448 F.3d 1357, 1366-67 (Fed. Cir. 2006). Conversely, we have repeatedly stated that actual "possession" or reduction to practice outside of the specification is not enough. Rather, as stated above, it is the specification itself that must demonstrate possession. And while the description requirement does not demand any particular form of disclosure, Carnegie Mellon Univ. v. Hoffmann-La Roche Inc., 541 F.3d 1115, 1122 (Fed. Cir. 2008), or that the specification recite the claimed invention in haec verba, a description that merely renders the invention obvious does not satisfy the requirement, Lockwood v. Am. Airlines, 107 F.3d 1565, 1571-72 (Fed. Cir. 1997).”
“For example, a generic claim may define the boundaries of a vast genus of chemical compounds, and yet the question may still remain whether the specification, including original claim language, demonstrates that the applicant has invented species sufficient to support a claim to a genus. The problem is especially acute with genus claims that use functional language to define the boundaries of a claimed genus. In such a case, the functional claim may simply claim a desired result, and may do so without describing species that achieve that result. But the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus.
Applicants have not characterized a representative species of gluten peptide antigen much less the antigen complex falling within the claims, and to which the “bispecific antibodies” have been shown to bind with any degree of specificity much less possess therapeutic activity in treating celiac disease, in vivo.
Written Description
9. Claims 48-77 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims 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.
Claim interpretation
Claims 48-60 are drawn to any bispecific antibody comprising a 1st VH/VL (anti-HLA-DQ2.5/1st gluten peptide) and a 2nd VH/VL (anti- HLA-DQ2.5/2nd gluten peptide) and having at least 95% identity to the 1st reference VH/VL and the 2nd reference VH/VL for any one of elements (1)-(14). None of the dependent claims identity the residues or domains in which the variation occurs. None of the dependent claims identity whether the variation includes substitutions, insertions, deletions, or combinations thereof. Notably, the genus of bispecific antibodies is required to bind not only HLA-DQ2.5/gluten peptide complexes but to effectuate a therapeutic response in an individual towards the treatment of celiac disease, in vivo.
Applicants have not shown for a reasonable number of embodiments which of the antibodies according to claims 48-60 are specific and/or cross-reactive for the first and second gluten peptides [that] are the same or different and [that] are independently selected from the following list: a 33mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 201, an alpha 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 182, an alpha 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 183, a gamma 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 184 or 206, a gamma 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 175, 185 or 207, an omega 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 186 or 204, an omega 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 187 or 204, a BC hordein peptide comprising the amino acid sequence of SEQ ID NO: 176, 188 or 205, an alpha 3 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 189, an alpha lb gliadin peptide comprising the amino acid sequence of SEQ ID NO: 190, a gamma 4a gliadin peptide comprising the amino acid sequence of SEQ ID NO: 191 or 209, a gamma 4b gliadin peptide comprising the amino acid sequence of SEQ ID NO: 192, an avenin 1 peptide comprising the amino acid sequence of SEQ ID NO: 193, an avenin 2 peptide comprising the amino acid sequence of SEQ ID NO: 194, an avenin 3 peptide comprising the amino acid sequence of SEQ ID NO: 195, a hordein 1 peptide comprising the amino acid sequence of SEQ ID NO: 196, a hordein 2 peptide comprising the amino acid sequence of SEQ ID NO:
197, a secalin 1 peptide comprising the amino acid sequence of SEQ ID NO: 198, a secalin 2 peptide comprising the amino acid sequence of SEQ ID NO: 199, and a 26mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 202. 57. (New) The method of claim 48, wherein (i) the first arm has binding activity to each of at least two different HLA-DQ2.5/gluten peptide complexes,(ii) the second arm has binding activity to each of at least two different HLA- DQ2.5/gluten peptide complexes, and (iii) the gluten peptides in the at least two complexes of (i) include at least two gluten peptides from the group below, and (iv) the gluten peptides in the at least two complexes of (ii) include at least two gluten peptides from the group below, and can be the same or different than the gluten peptides in the at least two complexes of (i): a 33mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 201, an alpha 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 182, an alpha 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 183, a gamma 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 184 or 206, a gamma 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 175, 185 or 207, an omega 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 186 or 204, an omega 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 187 or 204, a BC hordein peptide comprising the amino acid sequence of SEQ ID NO: 176, 188 or 205, an alpha 3 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 189, an alpha lb gliadin peptide comprising the amino acid sequence of SEQ ID NO: 190, a gamma 4a gliadin peptide comprising the amino acid sequence of SEQ ID NO: 191 or 209, a gamma 4b gliadin peptide comprising the amino acid sequence of SEQ ID NO: 192, an avenin 1 peptide comprising the amino acid sequence of SEQ ID NO: 193, an avenin 2 peptide comprising the amino acid sequence of SEQ ID NO: 194, an avenin 3 peptide comprising the amino acid sequence of SEQ ID NO: 195, a hordein 1 peptide comprising the amino acid sequence of SEQ ID NO: 196, a hordein 2 peptide comprising the amino acid sequence of SEQ ID NO: 197, a secalin 1 peptide comprising the amino acid sequence of SEQ ID NO: 198, a secalin 2 peptide comprising the amino acid sequence of SEQ ID NO: 199, and a 26mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 202.
Claims 61-69 are drawn to any bispecific antibody comprising a 1st HC/LC (anti-HLA-DQ2.5/1st gluten peptide) and a 2nd HC/LC (anti- HLA-DQ2.5/2nd gluten peptide) and having at least 95% identity to the 1st reference HC/LC and the 2nd reference HC/LC for any one of elements (1)-(14). None of the dependent claims identity the residues or domains in which the variation occurs. None of the dependent claims identity whether the variation includes substitutions, insertions, deletions, or combinations thereof. Notably, the genus of bispecific antibodies is required to bind not only HLA-DQ2.5/gluten peptide complexes but to effectuate a therapeutic response in an individual towards the treatment of celiac disease, in vivo.
Applicants have not shown for a reasonable number of embodiments which of the antibodies according to claims 61-69 are specific and/or cross-reactive for the first and second gluten peptides [that] are the same or different and [that] are independently selected from the following list: a 33mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 201, an alpha 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 182, an alpha 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 183, a gamma 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 184 or 206, a gamma 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 175, 185 or 207, an omega 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 186 or 204, an omega 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 187 or 204, a BC hordein peptide comprising the amino acid sequence of SEQ ID NO: 176, 188 or 205, an alpha 3 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 189, an alpha lb gliadin peptide comprising the amino acid sequence of SEQ ID NO: 190, a gamma 4a gliadin peptide comprising the amino acid sequence of SEQ ID NO: 191 or 209, a gamma 4b gliadin peptide comprising the amino acid sequence of SEQ ID NO: 192, an avenin 1 peptide comprising the amino acid sequence of SEQ ID NO: 193, an avenin 2 peptide comprising the amino acid sequence of SEQ ID NO: 194, an avenin 3 peptide comprising the amino acid sequence of SEQ ID NO: 195, a hordein 1 peptide comprising the amino acid sequence of SEQ ID NO: 196, a hordein 2 peptide comprising the amino acid sequence of SEQ ID NO:
197, a secalin 1 peptide comprising the amino acid sequence of SEQ ID NO: 198, a secalin 2 peptide comprising the amino acid sequence of SEQ ID NO: 199, and a 26mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 202. 57. (New) The method of claim 48, wherein (i) the first arm has binding activity to each of at least two different HLA-DQ2.5/gluten peptide complexes,(ii) the second arm has binding activity to each of at least two different HLA- DQ2.5/gluten peptide complexes, and (iii) the gluten peptides in the at least two complexes of (i) include at least two gluten peptides from the group below, and (iv) the gluten peptides in the at least two complexes of (ii) include at least two gluten peptides from the group below, and can be the same or different than the gluten peptides in the at least two complexes of (i): a 33mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 201, an alpha 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 182, an alpha 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 183, a gamma 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 184 or 206, a gamma 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 175, 185 or 207, an omega 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 186 or 204, an omega 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 187 or 204, a BC hordein peptide comprising the amino acid sequence of SEQ ID NO: 176, 188 or 205, an alpha 3 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 189, an alpha lb gliadin peptide comprising the amino acid sequence of SEQ ID NO: 190, a gamma 4a gliadin peptide comprising the amino acid sequence of SEQ ID NO: 191 or 209, a gamma 4b gliadin peptide comprising the amino acid sequence of SEQ ID NO: 192, an avenin 1 peptide comprising the amino acid sequence of SEQ ID NO: 193, an avenin 2 peptide comprising the amino acid sequence of SEQ ID NO: 194, an avenin 3 peptide comprising the amino acid sequence of SEQ ID NO: 195, a hordein 1 peptide comprising the amino acid sequence of SEQ ID NO: 196, a hordein 2 peptide comprising the amino acid sequence of SEQ ID NO: 197, a secalin 1 peptide comprising the amino acid sequence of SEQ ID NO: 198, a secalin 2 peptide comprising the amino acid sequence of SEQ ID NO: 199, and a 26mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 202.
Claims 70-77 are drawn to any bispecific antibody comprising a 1st VHCDR1-3/VLCDR1-3 (anti-HLA-DQ2.5/1st gluten peptide) and a 2nd VHCDR1-3/VLCDR1-3 (anti- HLA-DQ2.5/2nd gluten peptide) of any one of elements (1)-(14). Notably, the genus of bispecific antibodies is required to bind not only HLA-DQ2.5/gluten peptide complexes but to effectuate a therapeutic response in an individual towards the treatment of celiac disease, in vivo.
Applicants have not shown for a reasonable number of embodiments which of the antibodies according to claims 70-77 are specific and/or cross-reactive for the first and second gluten peptides [that] are the same or different and [that] are independently selected from the following list: a 33mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 201, an alpha 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 182, an alpha 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 183, a gamma 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 184 or 206, a gamma 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 175, 185 or 207, an omega 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 186 or 204, an omega 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 187 or 204, a BC hordein peptide comprising the amino acid sequence of SEQ ID NO: 176, 188 or 205, an alpha 3 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 189, an alpha lb gliadin peptide comprising the amino acid sequence of SEQ ID NO: 190, a gamma 4a gliadin peptide comprising the amino acid sequence of SEQ ID NO: 191 or 209, a gamma 4b gliadin peptide comprising the amino acid sequence of SEQ ID NO: 192, an avenin 1 peptide comprising the amino acid sequence of SEQ ID NO: 193, an avenin 2 peptide comprising the amino acid sequence of SEQ ID NO: 194, an avenin 3 peptide comprising the amino acid sequence of SEQ ID NO: 195, a hordein 1 peptide comprising the amino acid sequence of SEQ ID NO: 196, a hordein 2 peptide comprising the amino acid sequence of SEQ ID NO:
197, a secalin 1 peptide comprising the amino acid sequence of SEQ ID NO: 198, a secalin 2 peptide comprising the amino acid sequence of SEQ ID NO: 199, and a 26mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 202. 57. (New) The method of claim 48, wherein (i) the first arm has binding activity to each of at least two different HLA-DQ2.5/gluten peptide complexes,(ii) the second arm has binding activity to each of at least two different HLA- DQ2.5/gluten peptide complexes, and (iii) the gluten peptides in the at least two complexes of (i) include at least two gluten peptides from the group below, and (iv) the gluten peptides in the at least two complexes of (ii) include at least two gluten peptides from the group below, and can be the same or different than the gluten peptides in the at least two complexes of (i): a 33mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 201, an alpha 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 182, an alpha 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 183, a gamma 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 184 or 206, a gamma 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 175, 185 or 207, an omega 1 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 186 or 204, an omega 2 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 187 or 204, a BC hordein peptide comprising the amino acid sequence of SEQ ID NO: 176, 188 or 205, an alpha 3 gliadin peptide comprising the amino acid sequence of SEQ ID NO: 189, an alpha lb gliadin peptide comprising the amino acid sequence of SEQ ID NO: 190, a gamma 4a gliadin peptide comprising the amino acid sequence of SEQ ID NO: 191 or 209, a gamma 4b gliadin peptide comprising the amino acid sequence of SEQ ID NO: 192, an avenin 1 peptide comprising the amino acid sequence of SEQ ID NO: 193, an avenin 2 peptide comprising the amino acid sequence of SEQ ID NO: 194, an avenin 3 peptide comprising the amino acid sequence of SEQ ID NO: 195, a hordein 1 peptide comprising the amino acid sequence of SEQ ID NO: 196, a hordein 2 peptide comprising the amino acid sequence of SEQ ID NO: 197, a secalin 1 peptide comprising the amino acid sequence of SEQ ID NO: 198, a secalin 2 peptide comprising the amino acid sequence of SEQ ID NO: 199, and a 26mer gliadin peptide comprising the amino acid sequence of SEQ ID NO: 202.
AS discussed herein above under section 7, the genus of gluten peptides is a reach-through and for what Applicants have not shown themselves to be in possession of at the time of filing.
Here, the language in the claims referring to a sequence identity “at least 95% identical” at least encompasses the VH/VL domains or the HC/CL for the anti-HLA-DQ2.5/gluten peptides antibodies, where the genus of all possible gluten peptides is known-and-yet to be discovered, wherein for both the VH and VL CDR1-3 and/or frameworks 1-4 are potential sites of variation and without limitation. The interpretation encompasses a genus of antibody variants beyond those taught in the specification that are required to bind HLA-DQ2.5/gluten peptide complexes and to effectuate a therapeutic response in an individual having celiac disease. Because applicant seeks patent protection for all such methods, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
Applicants disclosure defines % identity as excluding conservative substitutions as part of the sequence identity
[0342] “Percent (%) amino acid sequence identity” with respect to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the reference polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity.
Applicants disclosure defines substitutions of amino acid as variants in the variable domains at
[0030] [1-2] The multispecific antigen-binding molecule of [1-1], which comprises at least one amino acid substitution in a variable region of the heavy chain; at least one amino acid substitution in a constant region of the heavy chain; at least one amino acid substitution in a variable region of the light chain; and at least one amino acid substitution in a constant region of the light chain.
Applicants disclosure defines deletions of amino acid as variants in the heavy chains
[0082] the first heavy chain further comprises glutamic acid at position 419 (EU numbering), and proline at position 445 (EU numbering), and an amino acid deletion at positions 446 and 447 (EU numbering); and the second heavy chain further comprises lysine at position 196 (EU numbering), proline at position 445 (EU numbering), and an amino acid deletion at positions 446 and 447 (EU numbering).
Applicants disclosure defines the modifications for amino acids in the antibody structures as deletions, insertions and/or substitutions of residues:
[0351] Amino Acid Modifications
[0352] An antigen-binding molecule (or antibody) of the invention may comprise one or more modifications. Such modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody. Any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen-binding.
[0353] An antigen-binding molecule (or antibody) of the invention may comprise amino acid substitutions. Conservative substitutions are shown in Table 1-1 under the heading of “preferred substitutions.” More substantial changes are provided in Table 1-1 under the heading of “exemplary substitutions,” and as further described below in reference to amino acid side chain classes. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., antigen-binding.
[0386] In the present invention, antibody variable regions that are “functionally equivalent” are not particularly limited as long as they are antibody H-chain and/or antibody L-chain variable regions that satisfy the above-described conditions. Examples of such antibody variable regions include regions produced by introducing substitution, deletion, addition, and/or insertion of one or more amino acids (for example, 1, 2, 3, 4, 5, or 10 amino acids) into the amino acid sequences of the variable regions of Tables 1 to 3 mentioned above. A method well known to those skilled in the art for introducing one or more amino-acid substitutions, deletions, additions, and/or insertions into an amino acid sequence is a method of introducing mutations into proteins.
Thus, the percent variation may encompass any number and kind of amino acids that are natural or non-natural or even mimetics. The percent variation may encompass the presence of non-naturally occurring thiol groups, e.g., methionine or cysteine, which is potentially disadvantageous because these amino acids can lead to misfolding or mis-conjugation problems.
Here, all of the claims encompass anti-HLA-DQ2.5/gluten peptide complex antibodies, and variations to the VH and VL domains, in which the variable domains, including the complementarity determining regions (CDRs) could vary relative to the VLC and VHC and CDRs found in a reference antibody in addition to the VL frameworks and VH frameworks. The encompassed antibodies are allowed to vary relative to a reference or parental antibody at any position and with any modification. The genus encompassed by the claims is therefore very large and there is substantial variation within the genus.
State of the Relevant Art
By the time the invention was made, it was also well-established in the art that the formation of an intact antigen-binding surface on an antibody required the association of the complete heavy and light chain variable regions, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope (Almagro & Franssen, Frontiers in Bioscience, 13:1619-33 (2008) (PTO-892) (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While this overall architecture is shared among antibodies from a wide variety of sources (human, rat, mouse, rabbit), the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully discloses the generation of bispecific anti-HLA-DQ antibodies at [0322-0327].
Applicant’s specification fully discloses binding analysis of the bispecific anti-HLA-DQ antibodies at [0328-0330].
Applicant’s specification fully discloses binding analysis of the bispecific anti-HLA-DQ antibodies with PBMC cells at [0331-0333].
Applicant’s specification fully discloses binding analysis of 14 bispecific anti-HLA-DQ antibodies with gluten restricted TCR at [0335-0360]. Table 2-7 identifies the binding pairs for the corresponding bispecific antibody HLA-DQ /gluten peptide complexes in blocking an engineered T cell TCR response/activity. Those data establish cross-reactivity for some antibodies to some HLA-DQ /gluten peptide complexes. Those data establish that the breadth and scope of the claimed invention exceeds what Applicants are in possession of at the time of filing:
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Applicants specification relies on a single celiac-disease related bioassay (engineered T cell TCR activity) for testing of the bispecific antibodies to determine the therapeutic outcomes in treating celiac disease, in vivo.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional variants. One of ordinary skill in the art would not have known which residues could be modified nor by which amino acids (natural, non-natural, mimetic, conservative, etc.) while still maintaining selectivity and affinity, which could be conservatively changed much less which could not be changed at all.
Applicant has not provided a common structure sufficient to visualize the genus of antibody variants beyond those taught in the specification that are required to bind HLA-DQ2.5/gluten peptide complexes and to effectuate a therapeutic response in an individual having celiac disease.
Even in 2021, therapeutic antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researches were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even though the protein sequence of HLA-DQ2.5 was known in the art, the genus of gluten peptides forming a complex with HLA-DQ2.5, and to which the inventive antibodies are required to bind, exceeds what Applicants have shown themselves to in possession of. Because of the lack of structure/function correlation between the claimed antibodies and the HLA-DQ2.5/gluten peptide complex to which they bind, this would not have translated into knowledge of the genus of antibodies that could possibly engage the complex. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different antibody structures, which would support the premise that the inventors possessed the full scope of the claimed method inventions.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
10. Claims 48-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/697,831 (reference application US 20240400693). The reference application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/speciation with the claims for the instant application.
Ref claim 1:
A formulation for injection in which a solution comprising an anti-HLA-DQ2.5 antibody as an active ingredient is filled in a container, wherein the antibody comprises any one of (1) to (3) below:
(1) a first antibody variable region comprising complementarity determining region (CDR) 1 of SEQ ID NO: 129, CDR 2 of SEQ ID NO: 130, and CDR 3 of SEQ ID NO: 131; a second antibody variable region comprising CDR 1 of SEQ ID NO: 132, CDR 2 of SEQ ID NO: 133, and CDR 3 of SEQ ID NO: 134; a third antibody variable region comprising complementarity determining region (CDR) 1 of SEQ ID NO: 153, CDR 2 of SEQ ID NO: 154, and CDR 3 of SEQ ID NO: 155; and a fourth antibody variable region comprising CDR 1 of SEQ ID NO: 150, CDR 2 of SEQ ID NO: 151, and CDR 3 of SEQ ID NO: 152;
(2) a first antibody variable region comprising the amino acid sequence of SEQ ID NO: 88; a second antibody variable region comprising the amino acid sequence of SEQ ID NO: 90; a third antibody variable region comprising the amino acid sequence of SEQ ID NO: 95; and a fourth antibody variable region comprising the amino acid sequence of SEQ ID NO: 100; or
(3) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 42 and a first light chain comprising the amino acid sequence of SEQ ID NO: 43, and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 63 and a second light chain comprising the amino acid sequence of SEQ ID NO: 61.
Element (1) of ref claim 1 for a bispecific antibody is identical to instant claim 70 (5):
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Element (1) of ref claim 1 for a bispecific antibody is identical to instant claim 71:
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Element (2) of ref claim 1 for a bispecific antibody is identical to instant claims 48(5) and 50-53
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And instant claims 54(5) and 55(5), respectively:
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Element (3) of ref claim 1 for a bispecific antibody is identical to instant claim 61(5) and 62:
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And instant claims 63(5) and 64(5), respectively:
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This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. Claims 48-77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17, 32-36, 38 and 39 of copending Application No. 17/438,496 (reference application US 20220153847). The reference application is not afforded safe harbor under 35 USC 121 because it shares no continuity nor a restriction/speciation with the claims for the instant application.
The claim sets 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]).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
12. No claims are allowed.
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643