DETAILED ACTION
Applicant’s amendment and response received on 3/16/26 has been entered. Claims 5, 8-11, 13-18, 21-22, 25-26, 28, and 32-34 are pending in this application. Of these, claims 21-22 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/17/25.
Claims 5, 8-11, 13-18, 25-26, 28, and 32-34 are therefore currently pending and under examination based on the elected species of immunogenic peptide comprising an oxidoreductase motif and a (pro)insulin MHC class II peptide which is SEQ ID NO:26. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 3/16/26 is in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the information disclosure statement has been considered by the examiner and an initialed and signed copy of the 1449 is attached to this action.
Claim Interpretation
It is noted that the recitation in the claims where the oxidoreductase motif is Zm[CST]XnC or ZmCXn[CST], where the claim defines Z, m, X, and n, has further been interpreted in regards to the meaning of [CST] based on the specific disclosure present on page 17 of the instant specification which states:
Alternatives are indicated by listing the acceptable amino acids for a given position, between square brackets ('[]'). For example: [CST] stands for an amino acid selected from Cys, Ser or Thr.
Thus, based on the specific definition of [CST] as providing a specific list of alternatives for this amino acid position in the peptide motif limited to C, S, or T, the recitation of [CST] in the claims is considered to narrowly encompass only a C (Cys), an S (Ser), or a T (Thr) at the position indicated by the brackets in the recited oxidoreductase motifs.
Claim Rejections - 35 USC § 103
The rejection of claims 5, 8-11, 13-18, 25-26, 28, and 32-34 under 35 U.S.C. 103 as being unpatentable over WO 2018/162498 (September 13, 2018), hereafter referred to as Vander Elst et al., in view of Durinovic-Bello et al. (2006) PNAS, Vol. 103(31), 11683-11688, and Nomura et al. (2006) J. Immunogenet., Vol. 33, 117-122, is maintained. Applicant’s amendments to the claims and arguments have been fully considered and have not been found persuasive.
The applicant argues that Vander Elst et al. does not teach to administer the immunogenic peptide to a subject having a DR4 positive MHC class II HLA haplotype for treating diabetes. According to applicant, Vander Elst et al. doesn’t teach or suggest that certain subgroups of patients could respond better to treatment with immunogenic peptides than others. The applicant further argues that Durinovic-Bello et al. does not teach that a potent reduction of an immune response by modifying the epitope with an adjacent oxidoreductase motif would be predictable because, according to the applicant, Durinovic-Bello teaches that in one instance an n-terminal overhang of the core epitope LALEGSLQK stabilized peptide/HLA binding where as in another instance a different n-terminal overhang did not affect peptide/HLA binding but instead modulated the resulting cytokine phenotype following peptide-TCR interaction, citing page 11686, right column, of Durinovic-Bello et al. The applicant further argues that the good binding of an epitope to DRB1 does not imply that any treatment relying on an effect obtained by using peptide with an oxidoreductase motif would be predictable. In support of this argument, the applicant cites Galvez et al., submitted with the IDS filed on 3/16/26. The applicant cites certain sections of Galvez et al. which are purported to teach that affinity is not necessarily associated with therapeutic efficacy. In addition, the applicant argues that Durinovic-Bello states that higher concentrations of the human P-Ins peptide were required to activate human T cell hybridomas versus mouse T cell hybridomas. Finally, the applicant argues that Nomura et al. does not teach that a pro-insulin MHC class II T cell epitope coupled to an oxidoreductase motif would preserve the capacity of the epitope to bend to MHC class II receptor and that this modified epitope would reduce an autoimmune response in DR4 positive MHC class II haplotype patients.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Further, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In the instant case, Vander Elst et al., the primary reference, was cited for teaching an immunogenic peptide comprising an oxidoreductase motif and an MHC class II peptide derived from insulin, where the peptide may be a peptide with the sequence HCxxCSLQPLALEGSLQKRG, or more specifically a peptide with the sequence HCPYCSLQPLALEGSLQKRG which is identified as SEQ ID NO:26 by Vander Elst et al. and is 100% identical to the elected species of a peptide with the amino acid sequence of instant SEQ ID NO:26 (Vander Elst et al., pages 3-4, and 30). Vander Elst et al. teach the use of the immunogenic peptide for the treatment or prevention of type 1 diabetes or for reducing the symptoms of type 1 diabetes (Vander Elst et al., page 4). In particular, Vander Elst et al. teaches the injection of the immunogenic peptide into a patient in need thereof, and in particular to a patient with an autoimmune disease such as type 1 diabetes (Vander Elst et al., pages 16-17, ). Vander Elst et al. further teaches a pharmaceutical composition comprising a therapeutically effective dose of the peptide, where a dosage regimen for administration of the peptide, where the dosage regimen is between 50-1500 ug of the peptide, and preferably 100-1200 ug of the peptide (Vander Elst et al., page 17). Vander Elst et al. also teaches particular dosage regimens where the administration is a single dose or 2, 3, 4, 5, or more doses, where the low dose scheme comprises the subcutaneous administration of 50 μg of peptide followed by three consecutive injections of 25 μg of peptide, the medium dose scheme comprises the administration of 150 μg of peptide followed by three consecutive administrations of 75 μg of peptide, and the high dose scheme comprises the administration of 450 μg of peptide followed by three consecutive administrations of 225 μg of peptide (Vander Elst et al., pages 17-18). Vander Elst et al. further teaches that the pharmaceutical composition comprises a pharmaceutically acceptable carrier and an adjuvant (Vander Elst et al., pages 24-25). Thus, Vander Elst et al. clearly teaches that the insulin derived peptide SLQPLALEGSLQKRG coupled at the N-terminus to the oxidoreductase motif HCPYC is immunogenic and can be administered in vivo to a patient with diabetes for treatment of the disease. Further, in regards to applicant’s argument that Vander Elst et al. doe not teach that certain subgroups of patients could respond better to treatment with immunogenic peptides than others, it is noted that applicant is arguing a limitation which is not present in the claims as written. The claimed method is drawn to a method of “reducing the immune response to an auto-immune antigen selected from (pro)insulin or C-peptide in a patient or of treatment or prevention of type 1 diabetes in a patient” by administering a peptide comprising a (pro)-insulin MHC class II T cell epitope and an oxidoreductase motif to the patient, where the patient has been selected based on the presence of a DR4 positive MHC class II HLA haplotype. Note that the method is drawn alternatively to “reducing the immune response to an auto-immune antigen selected from (pro)insulin or C-peptide in a patient” OR “ treatment or prevention of type 1 diabetes in a patient”. The claimed method does not recite that patients with a DR4 MHC class II HLA haplotype respond better to the peptide than other patients with different haplotypes, and in the alternative method related to treatment of diabetes does not require any specific therapeutic responses in the patient at any particular dose of peptide.
Further, the rejection of recognized that Vander Elst et al., while teaching to administer an immunogenic peptide with the sequence of SEQ ID NO:26 for treating or preventing type 1 diabetes in a patient, does not specifically teach to administer the peptide to a patient which has been identified or selected as having a DR4 positive MHC class II HLA haplotype, and further does not specifically teach methods of determining the HLA class II haplotype of a diabetes patient. Durinovic-Bello et al. was cited to supplement Vander Elst et al. by teaching an immunodominant HLA DRB1*0401 (DR4)-restricted peptide which has residues 73-90 of insulin, where the peptide comprises the core sequence LALEGSLQK which is the insulin peptide portion of instant SEQ ID NO:26 (Durinovic-Bello et al., page 11683). Durinovic-Bello et al. teaches that there are self-reactive T cells in T1D autoimmunity and that the HLA DRB1*0401 (DR4)-restricted peptide which has residues 73-90 of insulin can serve as a therapeutic target for preventing or delaying diabetes in humans (HLA DRB1*0401 (DR4)-restricted peptide which has residues 73-90 of insulin, page 11683). Note that the complete sequence of the 73-90 peptide taught by Durinovic-Bello et al. is GAGSLQPLALEGSLQKRG, where LALEGSLQK is identified as the core epitope. The pro-insulin epitope present in SEQ ID NO:26 is SLQPLALEGSLQKRG. However, note that Durinovic-Bello et al. shows that the GAG positions at the N-terminus can be deleted or swapped with another amino acid while retaining DR4/TCR contact and T cell activation, including cytokine secretion (Durinovic-Bello et al., Figures 2 and 3). In particular, note that each of the residues G, A, and G at the N-terminus of the 73-90 peptide can be either removed to changed to other residues, including changing the G at -7 to P, the A at -6 to Y and the G at -5 to C which are the amino acids in the immediate flanking positions -7, -6, and -5 in SEQ ID NO:26, with no effect on T cell activation responses (Figures 2 and 3). Further, contrary to applicant’s argument, the comments on page 11686 of Durinovic-Bello et al. are not referring to an unpredictability in MHC binding or T cell activation by creating a fusion between the insulin peptide and a second peptide such as the oxidoreductase motif taught by Vander Elst et al. The statements on page 11686 of Durinovic-Bello et al. are referring the effect that flanking residues can have on the stability of the binding of a peptide to MHC and on T cell activation and cytokine response. Whether the affects of flanking residues may be different for a different peptide, Durinovic-Bello et al. clearly shows that removal of -7 to -5 position N-terminal flanking residues does not affect DR4 binding stability or T cell activation, and further that substitution of those residues with residues present in the -7 to -5 positions found in SEQ ID NO:26 also do not affect the binding of the peptide to DR4 or the activation of T cells. Thus, Durinovic-Bello et al. clearly teaches that the pro-insulin peptide epitope present in SEQ ID NO:26 binds to DR4 and does not teach or suggest that the addition of addition peptide residues, such as the oxidoreductase motif present in SEQ ID NO:26, would substantially alter or abrogate binding of the peptide to DR4 or prevent the peptide from interacting with peptide specific TCR. Furthermore, it is reiterated that Vander Elst clearly teaches that the sequence of SEQ ID NO:26 comprising an oxidoreductase motif and the DR4 binding (pro)-insulin peptide SLQPLALEGSLQKRG is in fact immunogenic, which requires the ability to not only bind to MHC but to be capable of peptide/MHC binding of TCR on T cells.
Turning to applicant’s citation of certain sections of Galvez et al. which are purported to teach that affinity is not necessarily associated with therapeutic efficacy, it is noted that the “affinity” that Galvez et al. is referring to in these quoted sections is not the affinity of a peptide for MHC, but rather the affinity of a TCR for a peptide/MHC complex. The statements in Galvez such as “affinity used as an estimate of immune response is questionable”, or the statement that “there is not(sic) a general and simple correlation between affinity (which is the quotient of two parameters) and response” highlighted by applicant are referring to the affinity of TCR present on T cells for peptide/MHC complexes and suggest that TCR affinity should not be relied upon as a predictive measure of therapeutic efficacy. However, the instant methods are not drawn to administration of T cells comprising any specific TCR with any specific affinity. The instant methods are drawn to the administration of peptide comprising a (pro)- insulin class II peptide epitope and an oxidoreductase motif to a patient. Thus, the teachings of Galvez et al. do not refute or bring into question the direct teachings of Vander Elst et al. or Durinovic-Bello et al.
In regards to Nomura et al., Nomura et al. was cited to further supplement both Vander Elst et al. and Durinovic-Bello et al. by teaching methods of HLA typing in diabetes patients which involve the use of DNA typing by PCR-RFLP, where a patient HLA-DR haplotypes can be determined (Nomura et al., page 118). Nomura et al. was not cited for teaching a particular pro-insulin peptide epitope or an oxidoreductase motif as these teachings were already supplied by Vander Elst et al.
Therefore, it is maintained that in view of the teachings and motivation provided by Vander Elst et al. to administer an immunogenic peptide with the sequence of SEQ ID NO:26 which comprises the immunodominant HLA DRB1*0401 (DR4)-restricted peptide taught by Durinovic-Bello et al. to a patient to treat or prevent diabetes, the teachings of Durinovic-Bello et al. for specific presentation of this epitope in the context of HLA DRB1*0401 for diabetes therapy, and the further teachings of Nomura et al. for methods of determining the HLA haplotype of a diabetes patient using PCR, it would have been prima facie obvious to the skilled artisan at the time of filing to determine whether a patient has the HLA DRB1*0401 allele which is capable of presenting the class II peptide present in SEQ ID NO:26 prior to administering the immunogenic peptide as taught by Vander Elst et al. in order to ensure the proper presentation of the peptide in the patient with a reasonable expectation of success. Likewise, as the immunogenic peptide taught by Vander Elst et al. binds to DR4 and not DR3, it would have been prima facie obvious to the skilled artisan at the time to give the immunogenic peptide to patients who are DR4 positive and DR3 negative as only the presence of DR4 is necessary for the desired therapeutic effect.
Double Patenting
The rejection of claims 5, 8-11, 13-18, 25-26, 28, and 32-34 on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 9,249,202, hereafter referred to as the ‘202 patent, in view of WO 2018/162498 (September 13, 2018), hereafter referred to as Vander Elst et al., in view of Durinovic-Bello et al. (2006) PNAS, Vol. 103(31), 11683-11688, and Nomura et al. (2006) J. Immunogenet., Vol. 33, 117-122, is maintained. Applicant’s amendments to the claims and arguments have been fully considered but have not been found persuasive in overcoming the rejection for reasons of record as discussed in detail below.
The applicant argues that their arguments in response to the 103 rejection above with regards to the teachings of Vander Elst et al., Durinovic-Bello et al., and Nomura overcome this rejection as well.
In response, applicant’s arguments concerning the teachings of Vander Elst et al., Durinovic-Bello et al., and Nomura have not been found persuasive for reason set forth in detail above. Further, the instant rejection is based on the claims of the ‘202 patent, which while broader than the instant claims, fully encompass the species recited in the instant claims. The applicant has not provided any arguments regarding the ‘202 patent claims. As such, it is maintained that the ‘202 patent claims, in view of Vander Elst et al., Durinovic-Bello et al., and Nomura et al., render the instant claims obvious.
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication from the examiner should be directed to Anne Marie S. Wehbé, Ph.D., whose telephone number is (571) 272-0737. If the examiner is not available, the examiner’s supervisor, Maria Leavitt, can be reached at (571) 272-1085. For all official communications, the technology center fax number is (571) 273-8300. Please note that all official communications and responses sent by fax must be directed to the technology center fax number. For informal, non-official communications only, the examiner’s direct fax number is (571) 273-0737. For any inquiry of a general nature, please call (571) 272-0547.
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Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634
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