DETAILED ACTION
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 .
Claim Status
Claims 17-18 and 20-85 have been cancelled and claims 3-4, 7, 10-15, 19, 86, and 88 have been amended as requested in the preliminary amendment filed 12/18/2023. Following the amendment, claims 1-16, 19, and 86-88 are pending in the instant application.
Claims 1-16, 19, and 86-88 are under examination in the instant office action.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Claims 1-16, 19, and 86-88 have an effective filing date of June 17, 2021 corresponding to PRO 63/211,752.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/18/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 10 is objected to because of the following informalities: the claim uses an abbreviation, ELISA, without first spelling out the abbreviation. Abbreviations need to be spelled out at their first appearance in the claims. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2-3, 5, 16, and 88 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 2 is drawn to a method of selecting peptides suitable for treating one or more patients for type 1 diabetes mellitus (T1DM) autoimmunity, comprising associating a selection of peptide fragments of preproinsulin to “a genotype and/or an autoimmunity phenotype associated with an antigen-specific immune response to the one or more peptide fragments or to one or more preproinsulin epitopes present within the selection”. As currently presented, it is unclear if the recitation of “associated with an antigen-specific immune response to the one or more peptide fragments or to one or more preproinsulin epitopes present within the selection” pertains only to the autoimmunity phenotype, or if an antigen-specific immune response is also associated with the genotype.
Claim 3 is drawn to the method of claim 1, wherein the selection is “a subset of peptide fragments from a larger set of therapeutic peptide fragments”. As currently presented, it is unclear as to what the “larger set of therapeutic peptide fragments” encompasses; it is unclear if the larger set of therapeutic peptide fragments drawn only to preproinsulin fragments or if the limitation drawn to fragments of any given therapeutic peptide. As such, one of ordinary skill in the art would not be able to reasonably ascertain the metes and bounds of the claim.
Claim 5 recites the limitation "the larger set of therapeutic peptide fragments" in line 4. There is insufficient antecedent basis for this limitation in the claim. Claim 5 depends from claim 4, which depends from claim 1. None of claims 1, 4, or 5 recite a limitation regarding a larger set of therapeutic peptide fragments, and as such the limitation "the larger set of therapeutic peptide fragments" lacks antecedent basis and renders the claim indefinite.
Claim 16 recites the phrase "e.g." at line 2, and this phrase renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is unclear as to if the recitation of “e.g., central memory T-cells, effector memory T-cells, and/or virtual memory T-cells” is meant to limit memory T-cells to those specific subpopulations, or of the subpopulations are merely exemplary and not intended to be limiting.
Claims 87-88 each incorporate “the composition of claim 86”. As detailed below, claim 86 is an improper dependent claims that does not incorporate all of the limitations of claim 1 from which it depends and therefore fails to further limit the method of claim 1. As such, the recitation of “the composition of claim 86” renders claims 87-88 indefinite, as one of ordinary skill in the art could not reasonably ascertain the metes and bounds of the claims.
Further regarding claim 88, the claim is drawn to a kit for treating T1DM autoimmunity, comprising “a plurality of containers, each container comprising one of the peptide fragments of the composition of claim 86, wherein the selection comprises at least two peptide fragments, optionally wherein each container comprises one of the peptide fragments of the larger set of therapeutic peptides of claim 3; and optionally, instructions for administration of the composition to a subject in need thereof”. As noted above for claim 3, which is incorporated by claim 88, it is unclear as to what the “larger set of therapeutic peptide fragments” encompasses; it is unclear if the larger set of therapeutic peptide fragments drawn only to preproinsulin fragments or if the limitation drawn to fragments of any given therapeutic peptide. As such, one of ordinary skill in the art would not be able to reasonably ascertain the metes and bounds of the claim.
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.
Claims 3 and 86 are 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 3 is drawn to the method of claim 1, wherein the selection is “a subset of peptide fragments from a larger set of therapeutic peptide fragments”. As such, claim 3 fails to further limit the method of claim 1, as claim 3 is broader than claim 1 wherein the selection is being made from a larger set of peptide fragments than specified in independent claim 1.
Claim 86 recites “[t]he composition of claim 1”. As such, claim 86 fails to (i) incorporate all of the limitations of claim 1 from which it depends and (ii) fails further limit the method of claim 1.
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 Interpretation
For the purposes of applying art, the following are noted with regard to claim interpretation:
With regard to claim 2, the claim is being interpreted such that each of the genotype and autoimmunity phenotype are associated with an antigen-specific immune response.
With regard to claim 3, the claim is being interpreted such that the preproinsulin fragments of the composition of claim 1 are a selected subset (i.e., a subset association with antigen-specific immune responses) of a larger set of preproinsulin fragments (i.e., the larger set of preproinsulin fragments comprises fragments not associated with antigen-specific immune responses).
With regard to claim 86, the claim is being interpreted as a composition comprising a selection of one or more preproinsulin fragments, wherein the selection of preproinsulin fragments are associated with a genotype of the subject and/or an autoimmunity phenotype of the subject determined by one or more stimulation assays, the genotype and/or the autoimmunity phenotype being associated with an antigen-specific immune response to the one or more peptide fragments or to one or more preproinsulin epitopes present within the selection.
The interpretation of claim 86 is subsequently applied to claims 87-88, which incorporate the composition of claim 86.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-11 and 86-87 are rejected under 35 U.S.C. 103 as being unpatentable over GB 2523399 A (herein after referred to as “Orban”) in view of non-patent literature by Durinovic-Bello et. al. (Diabetologia, 2004, 47, 439-450; herein after referred to as “Bello”).
Orban teaches a composition comprising therapeutically effective amounts of two or more overlapping fragments of any part of preproinsulin (wherein one fragment is antigenic) and a pharmaceutically acceptable carrier for use in the treatment or prophylaxis of insulin dependent type I diabetes mellitus is disclosed wherein the composition may act by causing immunological tolerisation to insulin, preproinsulin or proinsulin and thus alleviate the effects of autoimmune disease in the pathogenesis of diabetes via the generation of anti-insulin antibodies; the composition may comprise fragments of overlapping sequence of 1-20 residues, may be formulated with alum or Freund's adjuvant and may be provided in a kit together with a diagnostic test for diabetes and the composition may further comprise other peptide fragments and may comprise two antigenic fragments from preproinsulin (Abstract). Methods of treating type I diabetes are also disclosed (Id.). Orban teaches that a loss of self-tolerance to insulin, a primary autoantigen, may unleash autoaggressive T cells and initiates autoimmunity; successful interventions may be implemented by deleting the autoaggressive cells and/or boosting the regulatory population, in order to re-establish control and create a healthy balance (Paragraph 0070). Antigen challenge in an autoimmune setting may stimulate beneficial changes in T cell subsets (e.g., Th2 vs. Th1), in cytokine production, and/or in regulatory T cells induction and in practice, antigen-specific therapeutic approaches for autoimmune diseases may use putative self-antigens that have been implicated in the disease aetiopathogenesis; insulin, is a beta-cell specific major protein and is also moderately immunogenic when used alone, but there is a concern about hypoglycemia among other side effects and thus insulin related peptides can be a safer choice than insulin for human use, because they do not necessarily have a hypoglycemic effect (Paragraph 0071; emphasis added). The invention can employ a preproinsulin sequence that is structurally and/or functionally homologous to SEQ ID NO: 1 wherein homology can include 70-90% homology; analogous sequences can include preproinsulin sequences from non-human species, humans having mutated preproinsulin sequences or preproinsulin sequence polymorphisms, and synthetic peptide sequences comprising one or more preproinsulin epitopes or cross-reactive epitopes (Paragraph 0056). The invention utilizes preproinsulin fragments in immunomodulatory compositions, wherein (i) the fragments can be about 20 amino acids in length or can be another length or lengths, for example the fragments can be about 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9 and/or 8 amino acids in length and the composition in accordance with the invention can include fragments of uniform length (e.g., all about 20 amino acids in length) as well as distributions of lengths and (ii) the fragments include a first polypeptide fragment and a second polypeptide fragment that overlap by about 10 amino acids or the fragments include a first polypeptide fragment and a second polypeptide fragment that overlap by about 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 amino acids and the composition in accordance with the invention can include fragments of uniform overlap (e.g., all about 10 amino acids) as well as varying overlap; fragment lengths, or distributions thereof, can be selected to optimize an immunomodulatory effect (Paragraphs 0061-0062; emphasis added). The fragments include at least one internal preproinsulin epitope, or the fragments can include two or more preproinsulin epitopes wherein the epitopes can be selected to optimize an immunomodulatory effect; in another embodiment, each of the two or more overlapping fragments comprises a preproinsulin epitope (Paragraphs 0066-0068). Orban further teaches a kit for diagnosing and treating type 1 diabetes mellitus autoimmunity including (i) a type 1 diabetes mellitus autoimmunity diagnostic (e.g., autoantibody testing- anti-insulin IAA, anti GAD65, anti IA2 insulinoma antigen 2, anti Zn8-zink transporter 8 antibodies, T cell biomarkers, and the like); (ii) a therapeutically effective amount of a composition of the invention; and (iii) instructions for diagnosing a subject and administering the composition to the subject if the subject is in need thereof (Paragraph 0086; emphasis added). Treatment for type 1 diabetes mellitus autoimmunity including administering a therapeutically effective amount of the composition of any one of the compositions in accordance with the invention to a subject in need thereof; in another aspect, the invention provides a treatment for type 1 diabetes mellitus autoimmunity including (i) selecting a subject in need of a treatment for type 1 diabetes mellitus autoimmunity; and (ii) administering a therapeutically effective amount of the composition of any one of the compositions in accordance with the invention to the subject wherein selection of a patient in need of a treatment can include physical examination by a physician and/or laboratory tests (Paragraph 0091). A therapeutically effective amount can be (i) 5 micrograms to 10 milligrams, 0.5 to 4.0 milligrams, or any value there between; (ii) 5, 10, 25, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 350, 400, 450, 500, 600, 700, 800, or 900 micrograms, or any value there between; or (iii) 1.0, 1.25, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75, 3.0, 3.25, 3.5, 3.75, 4.0, 4.25, 4.5, 4.75, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10 milligrams, or any value there between (Paragraph 00101). In various embodiment, a therapeutically effective amount can be determined by the detection of beneficial immune response (e.g., Th2/Treg response) and/or by the detection of at least one clinical endpoint or at least one symptom reduction (Id.). Thus, Orban teaches immunogenic compositions useful in the treatment of T1DM wherein said compositions comprise one or more fragments, and/or one or more epitopes, of preproinsulin wherein said fragments (i.e., lengths or distributions) may be selected in order to optimize immunomodulatory effect (i.e., immune response). Orban further teaches methods of polypeptide (i.e., preproinsulin fragment) synthesis and purification (see Paragraphs 00104-00115); peptides are made as a monocomponent HPLC (Cl8 column) purified peptides (i.e., each peptide is made individually), synthesized in a protein-core laboratory on a Protein Synthesizer Model 433A from Applied Biosystems, using amino acid preparations from Peptide International (Paragraph 00105) and purified under sterile conditions using HPLC, wherein desired fraction(s) are pooled in sterile vials and lyophilized (Paragraph 00115). Orban further teaches vaccine formulations wherein, for example, the vaccine is a combination of a water-soluble preproinsulin 20-amino acid overlapping polypeptide mixture and incomplete Freund' s adjuvant solution and the injections/emulsions (e.g., the final drug products) are prepared as a kit; the two main components (e.g., peptides and adjuvant) in different sealed compartments (i.e., different containers) with a built in mechanism to prepare a fresh mix to be used within short period of time (e.g., days/weeks) (Paragraph 00119; emphasis added). Thus, one of ordinary skill in the art would recognize that for compositions wherein more than one preproinsulin fragment is selected, each fragment may be separately synthesized and separately stored until a fresh mix for use is needed.
However, Orban does not explicitly teach or suggest selecting preproinsulin fragments based on or based at least in part on a genotype of the subject and/or an autoimmunity phenotype of the subject determined by one or more stimulation assays, the genotype and/or the autoimmunity phenotype being associated with an antigen-specific immune response to the one or more peptide fragments or to one or more preproinsulin epitopes present within the selection. Orban also does not suggest determining autoimmune phenotype based on stimulation assays using PBMCs by characterizing cell proliferation and/or cytokine production. These deficiencies are remedied by Bello.
Bello discloses a study that analyses the phenotype and epitope recognition of preproinsulin reactive T cells in subjects with a high genetic risk of diabetes [HLA-DRB1*04, DQ8 with Ab+ (auto-antibody-positive) or without islet autoantibodies (control subjects)], and in HLA-matched diabetic patients wherein a preproinsulin peptide library approach was used to screen for cytokine profiles and epitope specificities in human peripheral blood lymphocytes, and CD4+CD45RA− and CD4+CD45RA+ T cell subfractions, representing memory and naive and recently primed T cells respectively (Abstract; emphasis added). In CD4+ T cell subsets the authors identified immunodominant epitopes and cytokine production patterns that differed profoundly between patients, Ab+ subjects and non-diabetic HLA-matched control subjects; in Ab+ subjects, a C-peptide epitope C13–29 and insulin B-chain epitope B11–27 were preferentially recognized, whereas insulin-treated Type 1 diabetic patients reacted to native insulin and B-chain epitope B1–16 (Id.). In peripheral blood lymphocytes of Ab+ subjects, an increase in T helper (Th) 1 (IFNγ, IL-2) and Th2 (IL-4) cytokines was detectable, whereas in CD45RA+ and CD45RA− subsets, IL-4 and IL-10 phenotypes dominated, compatible with the contribution of non-CD4 cells to IFNγ content (Id.; emphasis added). In insulin-treated Type 1 diabetic patients, naive and recently primed CD4+ cells were characterized by increased IFNγ, TNFα, and IL-5 (Id.; emphasis added). Thus, the data show that T cell reactivity to preproinsulin in CD45RA subsets is Th2- dominant in Ab+ subjects, challenging the Th1 paradigm in Type 1 diabetes; characteristic immunodominant epitopes and cytokine patterns distinguish diabetic patients and Ab+ subjects from HLA-matched healthy individuals, which could prove useful in monitoring of T-cell immunity in clinical diabetes intervention trials (Id.). To measure the level of TNFα, IFNγ, IL-2, IL-4, IL-5 and IL-10 secreted after stimulation with proinsulin, insulin and 21 overlapping PPI peptides: (i) 175 μl of supernatant was taken from each well on day 5 of culture followed by addition of 3H-TdR; (ii) supernatants of replicate cultures were pooled and stored at −20°C until assay; and (iii) they were analyzed according to the manufacturer’s instructions, using an antigen-capture ELISA (Page 442, Column 1, Cytokine Assay; emphasis added). After sorting of PBMC into naive and recently primed or memory Th-cell subsets, marked differences were observed in Ab+ subjects, compared to those of patients and control subjects (Fig. 2), with regard to Th1 type cytokines; IFNγ and TNFα were decreased in both cell subsets (p<0.0001) (Fig. 2), hence Th2 and T regulatory (Tr) phenotypes, characterized by IL-4 and IL-10, predominated in cell subsets of Ab+ subjects (Fig. 3) (Page 444, Last Paragraph Column 1 through First Paragraph Column 2). In memory cells of Ab+ subjects Th2/Tr responses to PPI peptides were greater than in patients and control subjects (p<0.0005 and p<0.005, Fig. 3) and in Ab+ subjects IL-5 concentrations were consistently lower in PBMC (p<0.0005) and in both Th-cell subsets (p<0.0001) than in the other two groups (Fig. 2) (Page 444, Column 2, First Partial and First Full Paragraph). In insulin-treated Type 1 diabetic patients naive and recently activated cells had increased production of IFNγ (p<0.0005), TNFα (p<0.0005), IL-5 (p<0.0005) and IL-10 (p<0.005) compared with control and Ab+ subjects (Fig. 2); consequently, mainly Th0 cytokine response phenotype to PPI peptides evolved, which was more frequent in patients than in Ab+ and control subjects (p<0.0005) (Fig. 3) (Page 444, Column 2, Second Full Paragraph). In memory cells of the patients Th2/Tr responses were more frequent than in control subjects (p<0.0005) and Th1 and Th0 responses were more frequent than in Ab+ subjects (p<0.005 and p<0.0005) (Id.). The study shows that in subjects with an increased genetic risk of Type 1 diabetes immune responses to PPI peptides are vigorous, and these are masked in unsorted PBMC largely due to the contribution of different cell types; in early stages of naturally occurring islet autoimmunity (Ab+ individuals) a massive increase in peripheral cytokine levels is present (except IL-5), which could not be detected in sorted Th-cell subsets, which indicates a contribution of cell types other than CD4+ cells, and in Th-cell subsets of Ab+ subjects low cytokine levels of predominantly Th2/Tr phenotype and increased proliferation in response to C13–29 and B11–27 are present (Page 448, Last Paragraph Column 1 through First Paragraph Column 2; emphasis added). After cessation of insulitis and exposure to exogenous insulin (Type 1 diabetic patients) an increase in IFNγ, TNFα, IL-5 and IL-10 levels and shift towards Th0 and Th2/Tr type of responses occur, accompanied by increased proliferation in response to B1–16 (Id.). The results support the hypothesis that human Type 1 diabetes is not exclusively associated with Th1-mediated autoimmunity, and that Th1 and Th2 cells, as well as their respective mediators participate and cooperate in pancreatic islet beta-cell destruction (protection); this indicates that different cell subsets are activated in naturally occurring islet autoimmunity (Ab+ subjects) compared to insulin-treated Type 1 diabetic patients or disease-control subjects (Page 448, Column 2, First Full Paragraph; emphasis added). Thus, Bello teaches that preproinsulin, and fragments thereof, are capable of eliciting immune responses, wherein stimulation assays (i.e., assays comprising stimulation of cells with preproinsulin and the subsequent analysis of cytokine release via ELISA) can be used to correlate preproinsulin fragments to autoimmunity phenotypes based on antigen-specific immune responses and cell proliferation.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, (i) Orban teaches immunogenic compositions/kits useful in the treatment of T1DM wherein said compositions/kits comprise one or more fragments, and/or one or more epitopes, of preproinsulin wherein Orban further suggests selecting fragments (i.e., lengths or distributions) in order to optimize immunomodulatory effect (i.e., immune response) and (ii) Bello teaches that preproinsulin, and fragments thereof, are capable of eliciting immune responses, wherein stimulation assays (i.e., assays comprising stimulation of cells with preproinsulin and the subsequent analysis of cell proliferation and/or cytokine release via ELISA) can be used to correlate preproinsulin fragments to autoimmunity phenotypes based on antigen-specific immune responses and cell proliferation (e.g., associated with IFNγ, TNFα, IL-2, IL-4, and/or IL-10).
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the methods and compositions taught by Orban wherein the preproinsulin fragments selected for use in the methods and compositions are optimized such that the preproinsulin fragments are evaluated for selection using stimulation assays to associate the fragments with a patient genotype or autoimmunity phenotype by way of antigen-specific immune response, as suggested by Bello. One would have been motivated to make such a modification because Orban suggests the selecting fragments in order to optimize immunomodulation and Bello teaches that stimulation assays performed with, for example, preproinsulin fragments can be used to determine antigen-specific immune responses and identify patient autoimmunity phenotypes therefrom. One of ordinary skill in the art would have a reasonable expectation of success because compositions comprising preproinsulin fragments and methods of using such composition in the treatment of T1DM are known in the art, optimization of fragment selection is desired, and methods of determining antigen-specific immune responses/autoimmunity phenotypes to preproinsulin fragments are also known in the art; selecting and using preproinsulin fragments, and compositions/kits thereof, specifically associated with antigen-specific immune responses and autoimmunity phenotype would reasonably be expected to treat T1DM.
Claims 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over GB 2523399 A (herein after referred to as “Orban”) and non-patent literature by Durinovic-Bello et. al. (Diabetologia, 2004, 47, 439-450; herein after referred to as “Bello”), as applied to claims 1-11 and 86-87 above, and further in view of non-patent literature by Whiteside et. al. (BioTechniques, 2002, 33 4-15; herein after referred to as "Whiteside").
The method of claim 7 is rendered obvious by Orban and Bello. However, it is noted that neither Orban or Bello explicitly teach or suggest characterizing cytokine production (i) via ELISpot assay, (ii) by measuring cytokine gene expression, nor (iii) fixing one or more populations of cells and staining for one or more cytokines within the cells. These deficiencies are remedied by Whiteside.
Whiteside teaches that ex vivo assays used for assessment of cytokine levels in body fluids or cellular supernatants fall into two general categories of (i) bioassays and (ii) immunoassays; immunoassays measure cytokine levels but not cytokine activity, and therefore although more widely used than bioassays, they are less informative (Page 5, Column 1, Second Paragraph). Cytokine production or cellular expression can also be measured at the protein or mRNA level in cells derived from body fluids or tissues or directly in tissue biopsies (Id.). Antibody-based assays are widely available in the form of familiar commercial kits; exemplified by enzyme-linked immunosorbent assays (ELISA), immunoassays are popular because of their acceptable specificity, sensitivity, rapid turnaround time, convenience, the ease of performance, and a relatively low cost (Page 5, Column 2, Second Full Paragraph). Multiparameter flow cytometry allows for detection of more than one cytokine in the same cell or for the precise definition of the lineage of cytokine producing cells by using antibodies to surface markers; another flow cytometry based method for cytokine secretion by single cells can be performed using whole blood or freshly separated PBMCs, wherein cells are stimulated with antigen for several hours to induce cytokine secretion by the antigen-responsive cells are incubated with a cytokine “catch” reagent, which is a conjugate of anti-CD45 and anti-cytokine antibodies which attaches to the surface of all leukocytes and, subsequently, a cytokine secreted by the antigen stimulated cell binds to the catch reagent and the cytokine-producing cells are visualized by a cytokine-specific detection antibody labeled with a fluorochrome and are quantified in a flow cytometer (Page 7, Column 2, First and Second Full Paragraphs). Enzyme-linked immunospot assay (ELISPOT), has been developed to determine the frequency of precursor cells in fresh or cultured populations of lymphocytes capable of releasing cytokines in response to stimulation by a cognate antigen; ELISPOT assays can be performed in several different formats, depending on the antigen used for vaccination and the expected frequency of antigen-specific precursor cells in the peripheral circulation, wherein the simplest format involves adding class I MHC-restricted peptides to the HLA-matched PBMCs for the duration of a 24-h assay and reading the number of spots, which directly reflects the frequency of the peptide-responsive T cells in the circulation and when such a frequency is low, PBMCs may be separated into CD8+ and CD4+ subsets, which are then tested individually in the ELISPOT assay (Page 8, Column 1, First and Second Paragraphs). Immunostaining of tissue sections or cells for cytokines has to be preceded by fixation, to ensure that the cytokines are not lost during the washing procedure, wherein it is noted that antibodies selected for immunostaining must be able to recognize and bind to a cytokine after fixation (Page 8, Column 2, First Partial Paragraph). An emerging technology features gene arrays to identify differentially expressed mRNA levels by comparing expression profiles of cytokines in different samples; this method can be used for the determination of cytokine genes upregulated in response to physiologic or pathologic conditions, external signals, or cellular stress wherein, for example, using a side-by-side hybridization, it is possible to simultaneously determine the profile of cytokine expression during activation, proliferation or differentiation of various cell types (Page 10, Column 2, Last Paragraph). Thus, Whiteside provides a review of various cytokine detection/quantification methodologies, including ELISA, ELISpot, flow cytometry, immunostaining (comprising fixing cells and staining for cytokines), and mRNA detection for measuring cytokine gene expression.
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to substitute the ELISA assay for characterizing cytokine production in a population of cells taught by Bello for other art-established methodologies including (i) an ELISpot assay, (ii) measuring cytokine gene expression (i.e., mRNA), or (iii) immunostaining comprising fixing the population of cells and staining for cytokines, as provided by Whiteside, or substitute the quantification of proliferation methodology of Bello (based on cytokine profiles) for another art-established methodology such as flow-cytometry, as provided by Whiteside. One would have been motivated to make such a substitution, and would have had a reasonable expectation of success in doing so, because all of the methodologies are established in the art as being useful for (i) cytokine characterization and/or (ii) cell quantification.
Further, it is known in the art that there are various methodologies that allow for the characterization of cytokine production and/or cell quantification. One of skill in the art could have substituted one known methodology for another, one cytokine characterization method or one cell quantification method for another, and the results of such methodologies would have been predictable.
Claims 16 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over GB 2523399 A (herein after referred to as “Orban”), non-patent literature by Durinovic-Bello et. al. (Diabetologia, 2004, 47, 439-450; herein after referred to as “Bello”), and non-patent literature by Whiteside et. al. (BioTechniques, 2002, 33 4-15; herein after referred to as "Whiteside"), as applied to claims 1-15 and 86-87 above, and further in view of non-patent literature by Nguyen et. al. (Journal of Immunological Methods, 2003, 275, 57-68; herein after referred to as "Nguyen").
The method of claim 15 is rendered obvious by Orban, Bello, and Whiteside. However, none of the cited reference explicitly teach or suggest quantifying one or more of NK cells, B cells, T cells, etc. (see claim 16) nor labeling such cells for one or more markers including CD4, CD8, CD3, etc. (see claim 19). This deficiency is remedied by Nguyen.
Nguyen teaches a method for flow cytometric analysis of T cell proliferation and activation, wherein flow cytometric analysis using four different fluorochromes were performed using CD45RA (ALB11)-PE, CD45RO (UCHL-1)-PE, CD25 (B1.49.9)-PE, CD71 (YDJ1.2.2)-PE, CD38 (T16)-PE, CD69 (TP1.55.3)-PE, CD3 (UCHT1)-ECD, CD4 (13B8.2)-FITC, CD8 (B9.11)-FITC antibodies (Page 60, Column 1, Section 2.6.2). CD3-/CD4- or CD3-/CD8- antibodies were used separately to distinguish Th cells or CTLs from the other cell populations and T cell activation was measured by the assessment of HLA-DR, CD45RO, CD25, CD38, CD69 and CD71 expression while dead cells were excluded with 7-AAD (Id.). T cell proliferation was determined by absolute cell counting; Fig. 2a and b shows the development of absolute cell count/μl of Th cells and CTLs over time, respectively (Page 61, Column 2, First Full Paragraph). With DC stimulation, the maximal T cell proliferation showing typical characteristics with a high intensity of side and forward scatter was recorded on day 7, at which time a five- to tenfold T cell expansion was observed, whereas T cells alone decreased continuously; significant differences in Th and CTL cell numbers between days 0, 3, 7 and 11 were confirmed by the MANOVA test with p < 0.0001 (Id.). Th cell activation was determined by analysis of the expression of CD25, CD71, CD45RO and HLADR; Fig. 3a and b shows the development of the activation molecules of Th cells over time (Page 61, Column 2, Second Full Paragraph). The expression of CD45RA (naive Th cells) and CD45RO (memory Th cells) developed inversely; during the stimulation period, Th cells lost their CD45RA expression and developed into memory Th cells with a high expression of CD45RO (Id.). Thus, Nguyen teaches that T cell proliferation and/or activation can be quantified using flow cytometry wherein cell populations are labeled for one or more of, for example, CD25, CD45RO, CD45RA, etc.
In the test of whether it is “obvious to try” there must be:
(1) a finding in the art at the time of filing of the invention that there had been a recognized problem or need in the art;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
In the instant case, (i) Orban teaches immunogenic compositions/kits useful in the treatment of T1DM wherein said compositions/kits comprise one or more fragments, and/or one or more epitopes, of preproinsulin wherein Orban further suggests selecting fragments (i.e., lengths or distributions) in order to optimize immunomodulatory effect (i.e., immune response) wherein antigen challenge autoimmune setting may stimulate beneficial changes in T cell subsets (e.g., Th2 vs. Thl), in cytokine production, and/or in regulatory T cells induction and in practice, antigen-specific therapeutic approaches for autoimmune diseases; (ii) Bello teaches that preproinsulin, and fragments thereof, are capable of eliciting immune responses, wherein stimulation assays (i.e., assays comprising stimulation of cells with preproinsulin and the subsequent analysis of cell proliferation and/or cytokine release via ELISA) can be used to correlate preproinsulin fragments to autoimmunity phenotypes based on antigen-specific immune responses and cell proliferation; (iii) Whiteside teaches various established methodologies for characterizing cytokine production and/or cell proliferation, wherein one methodology for quantifying cell proliferation includes flow cytometry; and (iv) Nguyen teaches a flow cytometry methodology for quantifying T cell proliferation wherein the method uses antibodies specific to T cell populations to separate specific subsets, wherein the markers include, for example, CD25, CD45RO, CD45RA.
Thus, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the methods rendered obvious by Orban, Bello, and Whiteside such that the methodology for quantifying cell proliferation comprises a flow cytometry methodology for quantifying T cell proliferation wherein the method uses antibodies specific to T cell populations to separate specific subsets, wherein the markers include, for example, CD25, CD45RO, CD45RA, as suggested by Nguyen. One would have been motivated to make such a modification because Orban suggests selecting fragments in order to optimize immunomodulation and that autoimmune setting may stimulate beneficial changes in T cell subsets (e.g., Th2 vs. Thl), in cytokine production, and/or in regulatory T cells induction and in practice, antigen-specific therapeutic approaches for autoimmune diseases. Whiteside suggests using flow cytometry to quantify cell populations and Nguyen teaches flow cytometry methodology for quantifying T cell proliferation wherein the method uses antibodies specific to T cell populations to separate specific subsets, wherein the markers include, for example, CD25, CD45RO, CD45RA. One of ordinary skill in the art would have a reasonable expectation of success because flow cytometric methods for quantifying cell populations are established in the art, and Nguyen specifically teaches using flow cytometry methodology for quantifying T cell proliferation wherein the method uses antibodies specific to T cell populations to separate specific subsets, wherein the markers include, for example, CD25, CD45RO, CD45RA; selecting and using preproinsulin fragments, and compositions/kits thereof, specifically associated with antigen-specific immune responses assessed by cytokine characterization and/or cell proliferation and quantification, specifically for T cells implicated in autoimmunity, would reasonably be expected to treat T1DM.
Conclusion
Claims 1-16, 19, and 86-88 are pending. Claims 1-16, 19, and 86-88 are rejected. No claims are allowed.
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/ALYSSA RAE STONEBRAKER/Examiner, Art Unit 1642
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