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 .
Application Status
Claims 29-54 are pending and examined on the merits herein.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. Please see Figures 4a and 6-10.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pages 65, 70-73, and 77. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 29-46, 48-52, and 54 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. The rationale for this determination is explained below:
Claims 29-45 and 48-52 are directed to a natural phenomenon because the claims recite a product of nature (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is:
Claim 29 – peptides comprising SEQ ID NO: 8 wherein one or more of the Q residues is replaced with an E residue; wherein the peptide is up to 40 amino acids in length. Claims 30-40 depend from claim 29 and provide additional sequences and substitutions for the peptide;
Claims 42-43 – a nucleic acid molecule that encodes for an isolated peptide as recited in claim 29;
Claims 41 and 44-45 – are further drawn to the peptide coupled to or associated with an MHC molecule and a composition of the same; and
Claims 48-52 – a binding protein, TCR or T or NK cell comprising the same, capable of recognizing the isolated polypeptide of claim 29.
Claim 46 is directed to a natural phenomenon and an abstract idea because the claims recite a natural phenomenon and an abstract idea (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: the peptides as recited in claim 29. The “abstract idea” is: “determining whether said peptide binds to T cells or antibodies from the patient.” Abstract ideas include mathematical concepts (including mathematical relationships, formulas, equations, and calculations), mental processes (including concepts performed in the human mind), and certain methods of organizing human activity (including managing personal behavior, relationships, or interactions between people). The “abstract idea” is:
Claim 46 – a method for diagnosing celiac disease comprising contacting the peptide with a sample from a patient and determining whether said peptide binds to T cells or antibodies from the patient.
This judicial exception is not integrated into a practical application because the contact between the peptide and the patient sample occurs prior to the determination and is already known in the art. There are no active steps incorporated after the “determination” is made.
The specification identifies that the claimed peptide epitopes are gliadin-omega (ω) epitopes that are preferably DQ2.5 restricted, and therefore can be bound to or presented by MHC class II/ HLA molecules, specifically HLA-DQ2.5 or DQ2.2 (page 14, lines 9-18). The instant specification further discloses that HLA-DQ2.5 and HLA-DQ2.2 have a known association with celiac disease (page 14, lines 19-22) and further that the immunogenicity of gluten peptides is greatly augmented through post-translational modification by the enzyme transglutaminase 2 (TG2), which by deamidation converts certain glutamine residues (Q) to glutamate (E), which presumably makes the peptides better suited for HLA-DQ2.5 binding by increasing the pMHC (peptide-major histocompatibility complex) stability (page 2, lines 23-28). The instant specification further teaches that while celiac disease is usually observed in reaction to wheat, barley and rye some patients also appear sensitive to oat (avenin) as well (page 2, lines 6-8). The instant specification further teaches that the present invention identifies epitopes from found in a diploid wild type of wheat (page 3, line 25). The instant specification further teaches that this epitope was not identified using conventional techniques but was identified due to a surprising finding that an antibody selected for its ability to interact with the immunodominant a-gliadin epitope, DQ2.5-glia-a1a, showed some properties, which upon further investigation suggested that the antibody might also be recognizing another T cell epitope in CeD patients which was then found to recognize SEQ ID NO: 8 (page 4, lines 1-8). The instant specification further teaches that given their proposed association with CeD, peptides or isolated peptides of the present invention can be found in or can be derived from a gluten protein, or a gliadin protein, which are therefore generally naturally occurring sequences, e.g. fragments of naturally occurring sequences or deamidated versions thereof (page 7, lines 26-29). Thus the peptides and binding proteins and cells expressing the binding proteins are naturally produced by humans and further a natural product. The peptides within humans would naturally be presented to CD4+ and CD8+ T cells in humans, which would in turn naturally produce T cells with TCR that bind to the epitope and antibodies that bind to the epitope.
Prior art teaches a known avenin peptide that fits the limitations of claim 29 that was verified with patient derived T cells that bound to it in vitro as seen in Ellis (European Journal of Gastroenterology & Hepatology, 20(6), 492–493; PTO-892) (page 493, col 1, para 3). Prior art also teaches use of peptides vaccines to desensitize patients to gliadin peptides as well as the use of antibodies to gliadin proteins as a means of diagnosing patients through serological testing as seen in Caio (BMC Med 17, 142 (2019); PTO-892).
There are no recited active steps of the claims to impose a meaningful limit on the scope of the claims. The claims of the compositions identified in the specification to contain products of nature in the human body wherein the peptides of SEQ ID NO: 8, 20, 22, 24-36 are verified with additional variants that are predicted, screened and verified. Thus, the isolated peptides are encoded by DNA by cells, wherein the peptides of SEQ ID NO: 8, 20, 22, 24-36 are produced by human cells, bound to HLA complexes, and presented to T-cells and would be a product of nature as would the resulting TCR and antibodies. The compositions of 3) would be unchanged wherein the composition is for a vaccine and the cells in 4) would be unchanged if isolated from circulating blood. Thus, there is no change in functional activity of the compositions. Contact of the peptide or peptide/MHC contact to a serological patient sample to test for binding for diagnosis is well known in the art.
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because:
A) no additional elements are present outside of the naturally occurring product of nature present in a human (“Step 2B”) in: 1) claims 29-40 – isolated peptides in SEQ ID NO: 8, 20, 22, 24-36 and elongated “derivative” peptides; 2) claims 42-43 – a nucleic acid molecule that encodes for the isolated peptide; 3) Claims 41 and 44-45- the peptide associated with an MHC; and 4) Claims 48-52 – a binding protein, TCR or T or NK cell comprising the same, capable of recognizing the isolated polypeptide of claim 29.
or
B) the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations (“Step 2B”) of: 5) Claims 46 – a method for diagnosing celiac disease comprising contacting the peptide with a sample from a patient and determining whether said peptide binds to T cells or antibodies from the patient;
Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims contain subject matter of a natural product and an abstract idea and do not amount to significantly more than the judicial exception(s).
Claim 54 is rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the statement “ the use” or “for use” of an invention without any meaningful steps for that use does not qualify as a process, machine, manufacture or composition of matter.
Claim Rejections - 35 USC § 112(b)
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.
Claims 30, 37, 39-40, and 54 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.
Claim 30 is drawn to a peptide comprising SEQ ID NO: 20, 22, or 24 or an amino acid sequence wherein one or more of said Q residues is replaced by an E residue. It is unclear if the “said Q residues” corresponds to any Q residue in the SEQ ID NO recited in the claim or if it is restricted to the Q residues within the “core sequence” of SEQ ID NO: 8.
Claim 37 recites wherein said peptide comprises SEQ ID NO: 37 or 38; as claim 37 depends from 29 it is unclear how the peptide can comprise SEQ ID NO: 37 or 38 when these sequences do not comprise SEQ ID NO: 8 or a modified version thereof as required by claim 29.
Claim 39 recites wherein said peptide comprises a G residue at position 10 or at the position corresponding to position 10. As claim 39 depends from claim 29 which requires a sequence of 9 residues it is unclear what position 10 or at the position corresponding to position 10 requires, is it the residue immediately after the 9-mer core sequence or is it position 10 in the up to 40 amino acid peptide as a whole? Claim 40 recites the same language as claim 39 and is therefore subject to the same analysis.
Claim 54 recites a method of producing the binding protein of claim 48, comprising the use of a conjugate or complex comprising a peptide comprising an epitope that comprises SEQ ID NO: 8. As the claim does not set forth any steps involved in the method/ process, it is unclear what method/ process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 37 rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 37 recites wherein said peptide comprises SEQ ID NO: 37 or 38 and claim 29 recites a peptide that comprises the amino acid sequence SEQ ID NO: 8 or wherein one or more of the Q residues is replaced with an E residue; wherein the peptide is up to 40 amino acids in length. As claim 37 depends from claim 29 but SEQ ID NO: 37 or 38 do not comprise SEQ ID NO: 8 or a modified version thereof as required by claim 29 claim 37 is not further limiting.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
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.
Claims 29-30, 32, and 39-54 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.
Regarding instant claim 29, the claim is drawn to peptides comprising SEQ ID NO: 8 wherein one or more of the Q residues is replaced with an E residue; wherein the peptide is up to 40 amino acids in length.
The issue with the claim is a genus of peptides comprising SEQ ID NO : 8 or a modified version thereof that is up to 40 amino acids in length when only 9 of those amino acids are defined and not where they are located within the 40 amino acid residues possible.
Claims 32 and 39-47 depend from claim 29 without resolving the issue identified above and are therefore included in this rejection.
Regarding instant claim 30, the claim is drawn to peptides comprising SEQ ID NO: 20, 22, or 24 wherein one or more of the Q residues is replaced with an E residue; or an amino acid sequence substantially homologous thereto wherein said substantially homologous sequence comprises a sequence with 1, 2, or 3 amino acid substitutions, additions, or deletions outside the core sequence of SEQ ID NO: 8.
The issue with the claim is a genus of peptides comprising SEQ ID NO : 20, 22, or 24 or a modified version thereof or an amino acid sequence substantially homologous thereto wherein said substantially homologous sequence comprises a sequence with 1, 2, or 3 amino acid substitutions, additions, or deletions outside the core sequence of SEQ ID NO: 8.
Regarding instant claim 48, a binding protein is claimed by its functional properties without a sequence, wherein the binding protein is claimed to bind the peptide epitope as recited in claim 29 coupled to or associated with MHC. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed epitope.
Claims 49-54 depend from claim 48 without resolving the issue identified above and are therefore included in this rejection.
Summary of the teachings of the specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant specification discloses that the term "T cell epitope" as used herein refers to an amino acid sequence which can bind to, be associated with, form a complex with, or be presented in an antigenic peptide groove of an appropriate MHC/HLA molecule, here an HLA-DQ 2.5 or HLA-DQ 2.2 molecule and that the term "B cell epitope" as used herein refers to an amino acid sequence that can be recognized by or bound by antibody molecules (or B cell receptors) (page 14).The specification identifies that the claimed peptide epitopes are gliadin-omega (ω) epitopes that are preferably DQ2.5 restricted, and therefore can be bound to or presented by MHC class II/ HLA molecules, specifically HLA-DQ2.5 or DQ2.2 (page 14, lines 9-18), with exemplary epitopes in Figure 9. The instant specification further discloses that HLA-DQ2.5 and HLA-DQ2.2 have a known association with celiac disease (page 14, lines 19-22) and further that the immunogenicity of gluten peptides is greatly augmented through post-translational modification by the enzyme transglutaminase 2 (TG2), which by deamidation converts certain glutamine residues (Q) to glutamate (E), which presumably makes the peptides better suited for HLA-DQ2.5 binding by increasing the pMHC (peptide-major histocompatibility complex) stability (page 2, lines 23-28). The instant specification further teaches that the present invention identifies epitopes from found in a diploid wild type of wheat (page 3, line 25). The instant specification further teaches that this epitope was not identified using conventional techniques but was identified due to a surprising finding that an antibody selected for its ability to interact with the immunodominant a-gliadin epitope, DQ2.5-glia-a1a, showed some properties, which upon further investigation suggested that the antibody might also be recognizing another T cell epitope in CeD patients which was then found to recognize SEQ ID NO: 8 (page 4, lines 1-8).
The instant specification demonstrates binding of the antibody to epitope candidates deemed physiologically relevant by trypsin digestion of T. Urartu sequences (Fig 8). Figure 9 is an assessment of the chymotrypsin digestion of the Wheat (Q9FUW7) and T. Urartu (A0A0E3SZN6). The instant specification further discloses that peptides comprising SEQ ID NO: 20, 28, 30 57-58 were tested for T cell activation (Fig 13) and that SEQ ID NO: 30 and 59 were further tested for intracellular IFN gamma generation of CD4 T cells (Fig 14-15).
The instant specification discloses that as used herein, the term "specifically binds" or "specifically recognizes" in the context of a peptide or epitope or complex or conjugate of the invention means those binding proteins (e.g. TCRs, antibodies or antigen binding domains of antibodies) that are capable of binding to a peptide or epitope of the invention, e.g. a peptide or epitope comprising the sequence PYPQQQQPY (SEQ ID NO:8) or a deamidated (or E residue containing) version thereof, or to a complex or conjugate of the invention, e.g. a complex or conjugate comprising said peptide or epitope of the invention loaded or presented on HLA-DQ2.5 or HLA-DQ2.2, and which do not cross-react (or do not bind) or do not significantly cross-react (or do not significantly bind) with other peptides, for example, other naked, isolated or unconjugated peptides or other peptides loaded or presented on HLA-DQ2.5 or HLA-DQ2.2 (e.g. other celiac disease associated peptides, or other gliadin or gliadin-derived peptides, or variants of gliadin derived peptides, or other gluten-derived peptides) (page 29). The binding proteins of the invention thus recognize or bind to residues found in the peptides or epitopes of the invention. Thus, although the binding proteins may also contact or interact with some residues outside the peptide or epitope, the binding proteins of the invention do not bind to MHC molecules alone, e.g. MHC molecules that are empty or unloaded with peptide (page 30).
One of ordinary skill in the art would understand that an “epitope” is a specific part of an antigen that is recognized and bound by an antigen binding molecule, typically by an antibody comprising 6 CDRs. The claim does not disclose the structure associated with the claimed function. Further the definition of an “epitope”, and the specific residues thereof, changes based on the binding molecule structure (e.g., antibody or TCR). The instant disclosure does not provide a structure-function correlation that would allow for a person of ordinary skill in the art to envision all of the distinct possible epitope residues, such that the obtained structure would result in the claimed functions/limitations.
The specification does not teach a structure activity relationship that would allow CDR residues to be determined that exhibit specificity with the omega gliadin epitopes recited.
The instant specification does disclose that the epitope comprising SEQ ID NO: 8 was identified from its ability to interact with the immunodominant a-gliadin epitope, DQ2.5-glia-a1a. The instant specification further teaches the CDR sequences of this antibody (Table page 35), and adds the restriction that the binding protein claimed does not bind HLA-DQ2.5, presenting the α1a gliadin peptide or the HLA-DQ2.2 presenting the same (page 31, lines 8-10). The instant specification further excludes an antibody comprising the CDRs in the table on page 36 and the VH and VL SEQ ID NO: 51-52) on page 37. There are no antibodies generated or tested in the instant specification.
Although there are numerous peptides recited in the instant specification only a few were generated and tested for immunogenicity.
No structure activity relationship has been determined that allows an effective omega gliadin antibody comprising a specific CDR sequence to be predicted based on recitation of a specific epitope of omega gliadin. Accordingly, the skilled artisan would not be able to discern a structure/function correlation for the binding protein to the claimed peptides other than those comprising all six CDRs.
Given the fact that the species that were described cannot be considered representative of the broad genus, Applicant was not in possession of the invention as claimed.
State of the Relevant Art
Prior art teaches a known avenin peptide that fits the limitations of claim 29 that was verified with patient derived T cells that bound to it in vitro as seen in Ellis (European Journal of Gastroenterology & Hepatology, 20(6), 492–493; PTO-892) (page 493, col 1, para 3). There is prolific prior art as to the epitopes of wheat and barley that are involved with celiac disease and a growing body of literature on the involvement of oats in this disease as well. Sollid (Immunogenetics, 2012, 64: 455-460; IDS filed 4/1/2026) teaches numerous epitopes recognized by CD4 T cells including DQ2.5 restricted epitopes (table 2); as well as an updated list of epitopes (Sollid, Immunogenetics, 2020, 72:85-88; IDS filed 4/1/2026) with multiple that match the instantly claimed modified SEQ ID NO: 8 except the last residue (table 1).
Anderson (US 8,835,603 B2; IDS filed 4/1/2026) teaches that predictive approaches have catalogued several hundred distinct putatively “toxic” gluten peptides based upon searches for homologues of known epitopes of intestinal T cell clones, or for gluten sequences predicted or proven to bind to HLA-DQ2 in vitro, having the motif favouring deamidation by tissue transglutaminase (tTG), and/or sequences resistant to proteolysis (col 1, lines 49-55).
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156pg 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3. Further, it is not possible to predict the amino acid sequence when an epitope is recited, because binding is dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Benchmarking B cell epitope prediction: Underperformance of existing methods, Protein Science (2005), 14:246–248 pg. 246). 3D structural analyses of antibody-epitope binding highlighting that the deficiency in the ability to predict the structural features of an antibody when the epitope is disclosed (Schreiber et al., 3D-Epitope-Explorer (3DEX): Localization of Conformational Epitopes within Three-Dimensional Structures of Proteins, Wiley Interscience, 42–44, 60596, pg. 879).
At the time of the filing of the instant application, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
It is well established in the art that the formation of an intact antigen-binding site in a TCR usually requires the association of the complete alpha and beta chain variable regions of a given TCR, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the TCR to its target peptide-MHC (pMHC) complex (e.g. Figure 4 of Rudolph, M. et. al. “How TCRs Bind MHCs, Peptides, and Coreceptors”, 2006 Ann. Rev. Imm. Vol. 24:419-446). While it is recognized that the CDR3 of each chain contributes the most to binding a specific peptide, CDR1 and 2 most strongly affect binding to the MHC and can affect the orientation of TCR binding relative the MHC groove as well as the contact between CDR3 and the peptide (see Table 2 rows 12 and 14 and page 449 paragraph 2, Figures 9-10). This peptide-determining CDR3 contact is formed by the contribution of both the alpha chain and the beta chain. Additionally, a study to increase antigen binding has shown that, unpredictably, mutations in all 6 CDRs can contribute to increases in affinity (Chlewicki et. al. “High-affinity, Peptide-specific T Cell Receptors can be Generated by Mutations in the CDR1, CDR2, or CDR3, Journal of Mol. Biol. 2005 Pages 223-239). Further, binding may require a difficult-to-predict structural change which may require conformational changes of CDR1 and 2 (See Rudolph page 439 paragraph 2). Thus, the prediction of CDR binding to the epitope is difficult to predict. Rudolph et. al. also teaches that although there may be a common docking model for TCR/pMHC binding, the structures determined have not revealed the basis for MHC restriction (page 456, paragraph 3).
Additionally, in the field of T cell receptor biology, including in the instant application, specific binding of the TCR to pMHC is often defined by the biological function of T cell activation. Rudolph et. al. teaches that thus far, determined CDR structures do not explain the large biological differences that arise from altered peptide ligands (page 448, paragraph 4), indicating the unpredictability of the CDR/pMHC interaction to cause T cell activation.
Claim Analysis Summary:
Regarding instant claim 29, the applicant does not have possession of the large genus of peptide epitopes possible to be generated comprising SEQ ID NO: 8 wherein one or more of the Q residues is replaced with an E residue; wherein the peptide is up to 40 amino acids in length.
Claims 32 and 39-47 depend from claim 29 without resolving the issue identified above and are therefore included in this rejection.
Regarding instant claim 30, the applicant does not have possession of the large genus of peptide epitopes possible to be generated comprising SEQ ID NO: 20, 22, or 24 wherein one or more of the Q residues is replaced with an E residue; or an amino acid sequence substantially homologous thereto wherein said substantially homologous sequence comprises a sequence with 1, 2, or 3 amino acid substitutions, additions, or deletions outside the core sequence of SEQ ID NO: 8.
Regarding instant claim 48, the Applicant does not have written description of an antibody is claimed based on the epitope to which it binds without a sequence. Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures and no structure activity relationship is identified in the instant disclosure that permits prediction of the antibody sequence based on the claimed epitope.
Claims 49-54 depend from claim 48 without resolving the issue identified above and are therefore included in this rejection.
Claim 53 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for methods of treating celiac disease with peptides, does not reasonably provide enablement for methods of treating or preventing celiac disease with a binding protein specific to the omega gliadin peptide. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
This is a scope of enablement rejection.
Nature of the invention/ Breadth of the claims.
The claim is drawn to a method of treating or preventing celiac disease in a subject comprising the step of administering an effective amount of a binding protein of claim 48 to said subject.
State of the prior art/ Predictability of the art. There is prior art demonstrating the effectiveness in administering a binding protein to an omega gliadin epitope associated with MHC in treating or preventing celiac disease. Caio (BMC Med 17, 142 (2019); PTO-892) teaches that celiac disease is an autoimmune disease on the rise that key genetic elements (HLA-DQ2 and DQ-8), auto-antigen (tissue transglutaminase) and a gluten environmental trigger (page 2, col 1, para 4). Balakireva (Nutrients. 2016; 8(10):644; PTO-892) teaches that it has been shown that glutenin-specific and gliadin-specific T-cells are cross reactive due to their directivity to repetitive sequence highly homologous in these proteins (section 4.1, para 1). Balakireva further teaches that such cross-reactivity contributes to the development and spread of T-cell response and inflammation and that celiac disease is characterized by neurological defects that may occur partly due to the cross-reactivity between antigliadin antibody and synapsin I protein (section 4.1, para 1). Balakireva further teaches that the current focus for celiac disease are looking to tolerance through prevention and treatment, as well as enzymatic treatment (section 5).
Working examples. There are no working examples provided in the instant disclosure for treatment or prevention of celiac disease using the binding protein of the instant claims in the instant disclosure.
Guidance in the specification.
The specification teaches that the only established treatment for celiac disease is a lifelong adherence to a gluten free diet (page 2, line 14). The specification teaches that the binding proteins of the present invention, e.g. antibody molecules, can be internalized into target cells or enable internalization into target cells. As the binding proteins of the present invention can target pMHC complexes on APCs, if the binding proteins are then internalized, this provides a convenient way for ensuring that the payload enters the target cells. Thus, depending on the payload chosen, the APCs expressing the pMHC target (e.g. APCs associated with CeD) can be killed or deleted (e.g. if the payload is a cytotoxic molecule or an appropriate inhibitory RNA/siRNA molecule) or gene or protein levels can be altered (e.g. if the payload is an inhibitory RNA/siRNA). Such conjugates therefore have therapeutic uses as described
herein, e.g. in the treatment of CeD. Alternatively, the binding proteins (e.g. antibodies, e.g. TCR-like antibodies, or T cell receptors) of the invention may be conjugated to or associated with a second binding protein with specificity for another entity, e.g. effector cells, which can then be recruited (page 26, lines 19-31).
The specification further teaches methods or diagnostic methods can also be used for determining or monitoring the efficacy of CeD therapy in a subject, wherein the binding of said peptide or epitope or complex or conjugate to T cells (or the activation of T cells) or the presence of said antibodies in the sample (as determined, for example, by the binding of said antibodies to said peptide or epitope or complex or conjugate), indicates that CeD is present (or still present). Typically such methods involve the analysis of samples at different time points, for example, before and after treatment, and/or at several time points after treatment, and a result which shows that the binding of said peptide or epitope or complex or conjugate to T cells (or the activation of T cells) or the presence of said antibodies in the sample (as determined, for example, by the binding of said antibodies to said peptide or epitope or complex or conjugate) is reduced, preferably measurably or significantly reduced, compared to a previous result on the same subject at a previous time point indicates that the CeD is improving or being treated effectively (page 43, lines 6-18). This indicates that a decrease in the amount of antibody that binds to the peptide indicates that the treatment with the peptide is effective.
Amount of experimentation necessary. An extensive amount of additional research is required in order to determine how effective administering a binding protein to an omega gliadin epitope associated with MHC to a subject would be at treating or preventing celiac disease and to determine to which population of subjects to administer the said treatment that could predictably prevent celiac disease development.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
Claim Rejections - 35 USC § 102
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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 29, 32, 48-52, and 54 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ellis (European Journal of Gastroenterology & Hepatology, 20(6), 492–493; PTO-892).
Regarding claims 29, 32, 48-52, and 54, Ellis teaches that T cells from small intestinal biopsies from oat intolerant patients were tested with synthetic avenin peptide PYPEQEEPY and found reactive in 5 patient samples (page 493, col 1, para 3).
The reactive T cells would be necessity comprise a TCR on the surface, that is comprised of a binding protein that specifically binds to the avenin peptide.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Ellis (European Journal of Gastroenterology & Hepatology, 20(6), 492–493; PTO-892) as applied to claims 29, 32, 48-52, and 54 above, and further in view of Anderson (US 8,835,603 B2; IDS filed 4/1/2026).
Examiner’s note: For the purpose of compact prosecution claim 37 is being examined as reciting: wherein the peptide further comprises an additional peptide comprising the amino acid sequence SEQ ID NO 37 or 38. This is in light of the instant specification that discloses that a second B cell epitope comprising SEQ ID NO: 37 or 38 found in the peptides of the invention (page 11, lines 27-31 to page 12, lines 1-4).
The teachings of Ellis regarding claims 29, 32, 48-52, and 54 are detailed above.
Ellis does not teach wherein the peptide composition further comprises a peptide of SEQ ID NO: 37 or 38.
Anderson teaches that the risk of anaphylaxis can be minimized and problems of formulation overcome using short linear, aqueous soluble peptides, encompassing sequences from the disease-relevant antigen recognized by pathogenic CD4 T cells (col 2, lines 64-67). Anderson further teaches that deamidated 15mers encompassing epitopes reported for intestinal T cell clones including SEQ ID NO: 37 (col 44, lines 41-49), SEQ ID NO: 37 has 100% sequence identity to instant claimed SEQ ID NO: 38. Anderson further teaches that given the large number of toxic gluten peptides, the inventors have sought to identify an optimal non-redundant set of immunodominant peptides from which a minimal mixture could be selected for use in a peptide-based immunotherapy capable of modulating the immune response of an individual to gluten that is useful in the treatment of celiac disease by specifically modifying the pathogenic T cell response to gluten and to therefore provide a vaccine effective against celiac disease, which could also be used in diagnosis and monitoring immunomodulatory therapeutics in celiac disease (col 3, lines 27-39). Anderson further teaches that
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to add an additional peptide as taught by Anderson to the peptide composition as taught by Ellis. The ordinary artisan would have been motivated to do so because Anderson teaches that the risk of anaphylaxis can be minimized and problems of formulation overcome using short linear, aqueous soluble peptides and that a non-redundant set peptides from which a minimal mixture could be selected for use in a peptide-based immunotherapy capable of modulating the immune response of an individual to gluten that is useful in the treatment of celiac disease by specifically modifying the pathogenic T cell response to gluten. The ordinary artisan has a reasonable expectation of success to make a composition comprising a mixture of peptides as taught by Ellis and Anderson.
Claims 41-44 is rejected under 35 U.S.C. 103 as being unpatentable over Ellis (European Journal of Gastroenterology & Hepatology, 20(6), 492–493; PTO-892) as applied to claims 29, 32, 48-52, and 54 above, and further in view of Høydahl (Gastroenterology, 2019, 156(5): 1428-1439; IDS entered 4/1/2026).
The teachings of Ellis regarding claims 29, 32, 48-52, and 54 are detailed above.
Ellis does not teach wherein the peptide is in a complex or conjugate with an MHC molecule; a nucleic acid comprising the peptide; a vector comprising the nucleic acid; or a composition of the MHC-peptide.
Regarding claims 41-44, Høydahl teaches generation of B cells expressing an HLA-DQ2.5 covalently attached to a gliadin peptide which was generated by cloning synthetic DNA into a retroviral plasmid, the cells were then transduced and stained for expression (retroviral transduction of A20 murine B cells; methods). Høydahl further teaches generation of monoclonal antibodies from these constructs as a means of assessing gluten peptide presentation and phenotypes in celiac disease patient gut samples (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to use DNA and a vector to generate an MHC-gliadin peptide as taught by Høydahl to the peptide composition as taught by Ellis. The ordinary artisan would have been motivated to do so because Høydahl teaches that the peptide-MHC complex can be successfully generated using a retroviral construct and that this construct can be used to generate monoclonal antibodies to be used in testing for celiac disease. The ordinary artisan has a reasonable expectation of success to make a vector construct comprising an MHC-gliadin peptide.
Claims 45-47 are rejected under 35 U.S.C. 103 as being unpatentable over Ellis (European Journal of Gastroenterology & Hepatology, 20(6), 492–493; PTO-892) and Høydahl (Gastroenterology, 2019, 156(5): 1428-1439; IDS entered 4/1/2026) as applied to claims 29, 32, 41-44, 48-52, and 54 above, and further in view of Caio (BMC Med 17, 142 (2019); PTO-892) and Celiac Disease Foundation (Nexvax2; published 01/09/2019; PTO-892)
The teachings of Ellis and Høydahl regarding claims 29, 32, 48-52, and 54 are detailed above.
Ellis and Høydahl do not teach wherein the peptide-MHC composition is a vaccine composition; a method of diagnosis utilizing the peptide-MHC complex; or a method of treatment comprising administration of an effective amount of the peptide.
Regarding claims 45 and 47, Caio teaches that the only effective treatment that is currently available is lifelong gluten free diet which comes with significant negative life impact (page 15, col 1, para 2). Caio further teaches that vaccines could represent a definitive cure for celiac disease and that there are current clinical studies using Nexvax2 to desensitize patients to gliadin peptides (page 15, col 2, para 1).
Regarding claim 46, Ciao teaches that the gold standard for CD diagnosis is represented by the combination of mucosal changes detected by duodenal biopsy and by positivity of serological tests (ant-tTG antibodies, anti-endomysium antibodies (EmA), and deamidated gliadin peptide (DGP) antibodies) (diagnosis, para 1; page 7). Ciao further teaches that current standard of care is based on the “four out of five rule”, which indicates that four out of five of the following criteria are enough to establish CD diagnosis: (1) typical signs and symptoms (diarrhea and malabsorption); (2) antibody positivity; (3) HLA-DQ2 and/or HLA-DQ8 positivity; (4) intestinal damage (i.e., villous
atrophy and minor lesions); and (5) clinical response to gluten free diet (diagnosis, para 2; page 7).
The Celiac Disease Foundation teaches that Nexvax2 has been granted Fast Track designation by the FDA to fill an unmet medical need. Celiac Disease Foundation further teaches that Nexvax2 has been designed to re-educate the body’s immune system to help protect celiac disease patients from the side effects associated with inadvertent exposure to gluten and potentially to resume a gluten containing diet.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instant application to generate an MHC-gliadin peptide vaccine composition, to treat for tolerization with the peptide, and to use the peptide as a tool for diagnosis of celiac disease as taught by Ciao and Celiac Disease Foundation using the peptide-MHC composition as taught by Ellis and Høydahl. The ordinary artisan would have been motivated to do so because Ciao teaches that the gold standard for CD diagnosis is represented by the combination of mucosal changes detected by duodenal biopsy and by positivity of serological tests; including gliadin antibodies. Caio further teaches that vaccines could represent a definitive cure for celiac disease further supported by NexVax2 which as taught by Celiac Disease Foundation has been designed to re-educate the body’s immune system to help protect celiac disease patients and further that it has been granted Fast Track designation by the FDA to fill an unmet medical need. The ordinary artisan has a reasonable expectation of success to use the peptide-MHC complex as tool for serological testing for an antibody and to generate an MHC-peptide vaccine composition that can then be used a as a method of treatment to induce tolerization.
Conclusion
No claims are allowed.
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/AMBER K FAUST/Examiner, Art Unit 1643
/GARY B NICKOL/Primary Examiner, Art Unit 1643
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