Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
1. Applicant’s amendment and response filed 6/24/25 is acknowledged and has been entered.
2. Applicant is reminded of Applicant's election without traverse of Group I and species of SEQ ID NO: 1 in Applicant’s response filed 8/28/24.
Claims 16, 18-23 and 26-30 are presently being examined. Claims 16, 18, 19, 21, 23 and 26-30 are independent claims.
3. Upon further consideration, the following rejection is set forth.
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.
4. Claims 16, 18, 23 and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more.
a) Claim 16 recites “An isolated peptide of sequence NQEESVRFDSDVGEFR (Hpep 1-SEQ ID NO: 1).”
Claim 23 recites in part “A vaccine composition comprising the peptide of claim 16”.
Claim 26 recites in part “A medicament comprising the peptide according to claim 16…or a vaccine composition comprising said peptide.”
BRI: The said isolated peptide is a subsequence (amino acid residues 28-43) of a naturally occurring HLA-DRb1-1 beta chain protein (see evidentiary reference UniProt Acc. No. A0A0AYCAL0, of record). There is no evidence of record that the recited peptide is present in nature, and thus the full length protein is the closest natural counterpart. The instant specification discloses that the term “vaccine composition” refers to a composition which can be administered to humans or to animals in order to induce an immune response (page 22 at lines 27-29). The instant specification does not disclose a limiting definition for the limitation “medicament” but does disclose that the medicament comprising the peptide can be for preventing or reducing transplant or GVHD in a patient in need thereof (e.g., paragraph spanning pages 27-28). The specification also discloses that the vaccine composition or the peptide may be for use as a medicament (e.g., page 3 at lines 22-24). Evidentiary reference Merriam-Webster dictionary (merriam-webster.com/dictionary/medicament, 2015, 7 pages) teaches that a medicament is a substance used in therapy. The instant specification further discloses that peptides of the invention are useful for achieving donor-specific immune tolerance or partial tolerance against a transplant in a patient who received, is receiving or is awaiting the receipt of the transplant or a graft (page 25 at lines 3-30 and page 26 at lines 1-25). The specification also discloses that the peptide is suitable for expanding and stimulating a population of CD8+CD45RClow Tregs in its immunosuppressive activity (page at lines 12-16 and page 36 at lines 9-10). However, the specification discloses for stimulating the said Tregs in vitro, culture with IL-2 and CpG ODNs or culture with IL-2 and IL-15 resulted in said expansion of the Tregs (e.g., paragraph spanning pages 54-55 and page 55 at lines 16-24). There is no evidence of record that the peptide alone, or a vaccine or medicament thereof only comprising the isolated peptide has the vaccine or medicament activity in vivo.
With regard to the 35 USC 101 Subject Matter Eligibility Guidelines, it is clear that the claims are drawn to a peptide composition of matter and thus meet step 1 of the analysis. Moving to step 2A prong 1, it is clear that the said peptide recited in the claims is a natural product. As is stated above, there is no evidence of record that the recited peptide is present in nature, and thus the full length protein is the closest natural counterpart. Note that the breaking of peptide bonds in a protein to form a peptide is not considered a markedly different characteristic. Moving on to step 2A prong 2, claim 16 does not recite additional elements that integrate the judicial exception into a practical application because no additional elements are recited. As regards claims 23 and 26 (in part), as discussed above, the limitations “vaccine” and “medicament” do not represent elements that integrate the judicial exception into a practical application because there is no evidence of record that the isolated peptide and the peptide alone that is present in the vaccine or medicament have markedly different properties (see discussion above in BRI section regarding the limitations “vaccine” and “medicament”), nor do the said limitations impart any structural difference. As regards step B, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the same reasons.
The Examiner notes that Applicant has support in the originally filed disclosure for an [immunologically effective amount of an] adjuvant included in the vaccine composition of the present invention (e.g., page 23 at lines 1-4).
b) Claim 18 recites “A nucleic acid molecule that encodes the peptide of claim 16.”
BRI: The instant specification does not disclose a limiting definition for “encodes”. However, evidentiary reference Merriam-Webster Dictionary (merriam-webster.com/dictionary/encode, 2025, 1 page) teaches that the definition of encode includes “to specify the genetic code for”. The specification does disclose “As used herein, the term “nucleic acid molecule” has its general meaning in the art and refers to a DNA or RNA molecule or any of the base analogues thereof …” (page 12 at lines 10-25). Note that the nucleic acid molecule that encodes the peptide encompasses a nucleic acid molecule having the nucleotide sequence coding for the full length protein from which the peptide derives (i.e., it contains the nucleotide sequence coding for the peptide).
With regard to the 35 USC 101 Subject Matter Eligibility Guidelines, it is clear that the claims are drawn to a nucleic acid composition of matter and thus meet step 1 of the analysis. Moving to step 2A prong 1, it is clear that the said peptide recited in the claims is a natural product. As is stated above the full length encoding sequence is encompassed by the claim. Also note that although the claimed nucleic acid molecule has a different structural characteristic than the naturally occurring gene, this structural characteristic is not considered a markedly different structural characteristic because it has the same nucleotide sequence as the natural gene. There is no markedly different functional characteristic. Moving to step 2A, prong 2, the claim does not recite additional elements that integrate the judicial exception into a practical application because no additional elements are recited. Moving to step 2B, the claim does not recite additional elements that amount to significantly more than the judicial exception for the same reason.
5. Applicant’s amendment and response filed 11/5/25 has overcome the prior rejection of record of claims 24, 25 and 28-33 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.
Applicant has canceled claims 24 and 25 and has amended base claim 28 to delete recitation of the limitation “MHC class I multimer loaded with said peptide”.
6. 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.
7. Claims 19, 23 and 26-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention.
The specification does not disclose how to make and/or use the instant invention:
a) a vaccine composition comprising the peptide of claim 16 or an immunoconjugate comprising an (any) antibody conjugated or fused to said peptide wherein the antibody is not one that is directed against a surface antigen of an antigen presenting cell (APC) (as recited in claim 23 in part);
b) a medicament comprising the peptide according to claim 16, an immunoconjugate comprising an antibody conjugated or fused to said peptide wherein the antibody is not one that is directed against a surface antigen of an antigen presenting cell (APC), or a vaccine composition comprising said peptide (as is recited in claim 26 in part);
c) a method for reducing transplant or graft rejection or GVHD in a patient in need thereof comprising administering the peptide according to claim 16, an immunoconjugate comprising an antibody conjugated or fused to said peptide wherein the antibody is not one that is directed against a surface antigen of an antigen presenting cell (APC), or a vaccine composition comprising said peptide (as is recited in claim 27 in part);
d) a method for expanding a population of CD8+CD45RClow Tregs and stimulating their immunosuppressive activity, comprising a step of culturing a population of CD8+CD45RClow Tregs with a culture medium comprising the peptide of claim 16 in the presence of a population of APCs (as is recited in claim 28);
e) a population of CD8+CD45RClow Tregs obtained by the method of claim 28 (as is recited in claim 29);
f) a method for reducing transplant or graft rejection or GVHD in a patient in need thereof, comprising administering to the patient the population of CD8+CD45RClow Tregs according to claim 29 (claim 30);
g) an immunoconjugate comprising an antibody conjugated or fused to the peptide of claim 16 that is not an antibody directed against a surface antigen of an antigen presenting cell (APC) (as is recited in claim 19).
As such, the claims encompass embodiments in which the vaccine composition or the medicament only comprises the peptide or for example, the peptide plus a pharmaceutically acceptable diluent or solvent (e.g., water or saline), and wherein there is no evidence of record that the peptide alone or in a diluent or solvent can act as a vaccine or a medicament when administered, including for reducing transplant, graft rejection, or GVHD in a patient in need thereof. As such the claims also encompass culturing conditions in which the APCs do not express HLA-A2 and also do not comprise IL-2 plus CpG ODNs or IL-2 plus IL-15, wherein it is unpredictable that said culturing conditions will result in the expansion of CD8+CD45RClow Tregs and stimulate their immunosuppressive activity, and wherein it is unpredictable that the said Tregs made in that way can reduce transplant or graft rejection or GVHD in a patient in need thereof.
The instant specification discloses that the term “vaccine composition” refers to a composition which can be administered to humans or to animals in order to induce an immune response (page 22 at lines 27-29). The instant specification does not disclose a limiting definition for the limitation “medicament” but does disclose that the medicament comprising the peptide can be for preventing or reducing transplant or GVHD in a patient in need thereof (e.g., paragraph spanning pages 27-28), and also discloses that the vaccine composition or the peptide may be for use as a medicament (e.g., page 3 at lines 22-24). Evidentiary reference Merriam-Webster dictionary (merriam-webster.com/dictionary/medicament, 2015, 7 pages) teaches that a medicament is a substance used in therapy. The instant specification further discloses that peptides of the invention are useful for achieving donor-specific immune tolerance or partial tolerance against a transplant in a patient who received, is receiving or is awaiting the receipt of the transplant or a graft (page 25 at lines 3-30 and page 26 at lines 1-25). The specification discloses that the composition may include an adjuvant (page 23 at lines 1-4), and that the route of administration may include, but are not limited to, inhalation, transdermal, oral, rectal, transmucosal, intestinal and parenteral (e.g., IM, SC, IV) (pages 23 at lines 11-15). The specification also discloses pharmaceutically acceptable carriers or excipients refers to any and all solvents or fillers or diluents (page 5 at lines 5-14), and that a patient refers to a mammal, preferably a human (page 5 at lines 15-23). The specification also discloses that the peptide is suitable for expanding and stimulating a population of CD8+CD45RClow Tregs in its immunosuppressive activity (page at lines 12-16 and page 36 at lines 9-10). However, the specification discloses for stimulating the said Tregs in vitro, culture with IL-2 and CpG ODNs or culture with IL-2 and IL-15 resulted in said expansion of the Tregs (e.g., paragraph spanning pages 54-55 and page 55 at lines 16-24). There is also no evidence of record that a vaccine or medicament only comprising the isolated peptide, or for example, one having a pharmaceutically acceptable diluent or solvent (e.g., water or saline) that has the vaccine or medicament activity in vivo.
In the working examples of the instant specification, autologous antigen presenting cells (i.e., dendritic cells) that are HLA-A2+ and also positive for undisclosed HLA class II molecules are contacted with the said peptide (see for example, Figure 2 and brief description of the drawings for Figure 2). The instant specification discloses at page 38, lines 17-18 that as used herein, the term “expanding” refers to the process of converting and/or amplifying a given population of cells such as CD8+ CD45RClow regulatory T cells.
The specification further discloses that “Peptides of the invention are useful for achieving tolerance or partial tolerance against the transplant upon transplantation of said transplant. As used herein, a “partial tolerance” is a partial immune tolerance which results in a reduced immune response. As used herein the term “immune response” includes T cell mediated and/or B cell mediated immune responses. Exemplary immune responses include T cell responses, e.g., cytokine production and cellular cytotoxicity, in addition, the term immune response includes immune responses that are indirectly effected by T cell activation, e.g., antibody production(humoral responses) and activation of cytokine responsive cells, e.g., macrophages. Immune cells in volved in the immune response include lymphocytes, such as B cells and T cells (CD4+, CD8+, Th1 and Th2 cells); antigen presenting cells (e.g., professional antigen presenting cells such as dendritic cells); natural killer cells; myeloid cells, such as macrophages, eosinophils, mast cells, basophils, and granulocytes. For instance, immune responses are involved in transplant rejection, as well as in the concomitant physiological result of such immune responses, such as for interstitial fibrosis, chronic grant arteriosclerosis, or vasculitis”(page 25 at lines 3-17). The specification further discloses that the immune tolerance or partial tolerance is a tolerance to a transplant or graft in a patient who received, is receiving or is awaiting the receipt of the transplant or graft, but it could also be donor specific immune tolerance referring to an immune tolerance to a transplant or graft from a donor with a MHC haplotype which contains the peptide (remainder of page 25 and continuing onto page 26 at lines 1-1), or recipient-specific immune tolerance referring to an immune tolerance induced in a transplant or graft from a donor towards a recipient (page 26 at lines 19-21). The specification also discloses that “As used herein, the term “immune tolerance” refers to a state of unresponsiveness of the immune system to substances or tissues that have the capacity to elicit an immune-response” (page 24 at lines 17-19). The specification discloses that the terms “transplant” and “graft” refer to any material from a donor subject that is inserted or to be inserted in a recipient subject (page 28 at lines11-13).
The specification discloses that SEQ ID NO: 1 (that is presently recited in the instant claims) as well as SEQ ID NO: 2 and 4 (that are not recited in the claims) were designed from four random human MHC class II alleles based on the sequences of the Du51 peptide (NREEYARFDSDVGEYR, derived from the b1 chain of rat RT1.Bu MHC class II) and an overlapping 12-mer peptide Bu31-10 (YLRYDSDVGEYR, derived from the b1 chain of rat MHC class II RT1.Du), both bearing the SDVGEYR motif at the C-terminal end (page 55 at lines 13-17). The specification discloses that in vitro expansion of the Tregs having the phenotype recited in the instant claims was tested with antigen presenting cells (APCs, dendritic cells in this instance) from the same individual with the SEQ ID NO: 2 peptide (i.e., APCs from an HLA-A2 positive individual) (page 56 at lines 3-16); however the specification does not disclose which class II HLA molecules are present on these APCs (with the length of the peptides being those that can bind in the open HLA class II peptide binding groove/cleft). Thus, it is not known if the peptide corresponding to the sequence of SEQ ID NO: 1 binds to a class II molecule or is endocytosed and processed in the class I HLA antigen processing pathway to a peptide subsequence that binds to HLA-A2.
Evidentiary reference WO2015150491 A1 (IDS reference) teaches that allograft tolerance induction in rats induced by the said Du51 peptide (including in tens of mg amounts administered by an implanted intraperitoneal mini osmotic pump over two weeks, e.g., at page 36 at lines 19-29) mentioned above (a 16-mer peptide of a length permissive for binding to a class II MHC molecule) and relevant to CD8+CD45RClow Tregs was dependent upon CD8+ T cells and MHC class I presentation (that generally bind peptides of 8-10 amino acid residues in length, although infrequent examples of longer peptides have been noted to bind thereto) (see for example, page 44 at lines 1-21). Said evidentiary reference also teaches that these said Tregs were induced/amplified by in vivo peptide treatment and may be responsible for tolerance induction. These Tregs displayed suppressive activity ex vivo, inhibiting effector CD4+ T cell proliferation, and inhibited IgG, G1, G2a and G2b alloantibodies in long-term surviving Du51-treated recipients as comparted to untreated rats or those rats that rejected their graft early (e.g., paragraph spanning pages 44-45). Note that in Figure 3A it appears that the IV administration of peptide did not produce a large effect.
Undue experimentation would be required of one skilled in the art to practice the instant invention. See In re Wands 8 USPQ2d 1400 (CAFC 1988).
8. A peptide consisting of the amino acid sequence set forth in SEQ ID NO: 1 is free of the prior art. A nucleic acid molecule coding for just the peptide consisting of the amino acid sequence set forth in SEQ ID NO: 1 is free of the prior art.
9. Claim 20 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Note that antibodies directed against a surface antigen of an antigen presenting cell as well as a nanoparticle are both known in the art to have adjuvant activity (the latter can be taken up by dendritic antigen presenting cells by endocytosis).
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARIANNE DIBRINO whose telephone number is (571)272-0842. The examiner can normally be reached on M, T, Th, F.
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If attempts to reach the examiner by telephone are unsuccessful, the Examiner’s supervisor, MISOOK YU can be reached on 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Marianne DiBrino/
Marianne DiBrino, Ph.D.
Patent Examiner
Group 1640
Technology Center 1600
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641