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 .
Terminal Disclaimer
The terminal disclaimer filed on August 21, 2026, disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Application No. 17/631,818 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 4, 7-9, 11-12, 14-15, 21-24, and 61-67 drawn to an HLA class II molecule) in the reply filed on May 22, 2025, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a single and specific HLA class II molecule as comprising a DP beta chain of SEQ ID NO: 3 where the amino acid at position 141 is Met and the amino acid at position 112 is Trp, and a DP alpha chain of SEQ ID NO: 6, where the HLA class II molecule is a DP1 allele, and where the DP beta chain is bound to a membrane of a cell and comprises an extracellular domain of a full length DP beta chain); and Species B (i.e., a single and specific complex of Species A as a single and specific HLA class II molecule and SEQ ID NO: 56 as a single and specific peptide) in the reply filed on May 22, 2025, is acknowledged.
Please note that in light of Applicant’s search, Species B is hereby withdrawn.
Additionally, please note that Species A is hereby withdrawn as the claimed invention is free of the prior art as further articulated below.
Status of Claims
Claims 1-61 were originally filed on January 31, 2022.
The amendment received on December 23, 2022, canceled claims 1-3, 5, 10, 13, 16-18, 20, 25-41, 43-44, 47-50, and 53-60; and amended claims 6-9, 11-12, 14-15, 19, 21, 23-24, 45-46, 51-52, and 61. The amendment received on May 22, 2025, canceled claims 42, 46, and 51-52; amended claim 4; and added new claims 62-67. The amendment received on 12/11/25, canceled claims 7-9, 11-12, 14, 62 and 67; and amended claims 4, 15, 61, 63, and 65-66. The amendment received on August 21, 2026, canceled claims 21, 23, and 63-65; amended claim 24; and added new claims 68-71.
Claims 4, 15, 19, 22, 24, 61, 66, and 68-71 are currently pending and are under consideration.
Priority
The present application claims status as a 371 (National Stage) of PCT/IB2020/057175 filed July 29, 2020, and claims priority under 119(e) to U.S. Provisional Application Nos. 62/880,496 filed on July 30, 2019, and 63/029,111 filed May 22, 2020.
Sequence Interpretation
For claim 4, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to SEQ ID NO: 3 with any N- and/or C-terminal additions. It is noted that SEQ ID NO: 3 has a Trp residue at position 112 and a Met residue at position 141.
For claim 15, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to SEQ ID NO: 4 with any N- and/or C-terminal additions.
For claims 22 and 70-71, please note that the Examiner is interpreting the scope as open-ended requiring 100% identity to SEQ ID NO: 6 or 8 with any N- and/or C-terminal additions.
For claim 61, please note that the Examiner is interpreting the scope as open-ended requiring two components; namely, an HLA class II molecule of claim 4, and one or more peptides comprising an amino acid sequence that requires 100% identity to one or more of SEQ ID NOs: 32-237 with any N- and/or C-terminal additions.
For claim 68, please note that the Examiner is interpreting the scope as open-ended where SEQ ID NO: 1 is a base sequence and requires an amino acid selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan at a position corresponding to residue 141 instead of valine, and an amino acid selected from alanine, valine, isoleucine, methionine, phenylalanine, and tyrosine at a position corresponding to residue 112 instead of leucine. Although claim 68 recites that the HLA class II molecule comprises a DP beta chain, the amino acid sequence of the DP beta chain is not limited as the beta chain does not require any specific amino acid sequence. Please see discussion in the 112(a) and (b) rejections below for further details. Thus, the scope of claim 68 encompasses any amino acid sequence including fragments as long as the sequence contains the two required structural limitations identified supra.
Response to Arguments
Applicant’s arguments, see Response, filed 8/21/26, with respect to claim objection of claims 23 and 65 have been fully considered and are persuasive. The objection of claims 23 and 65 as being a substantial duplicate thereof has been withdrawn.
Applicant’s arguments, see Response, filed 8/21/26, with respect to the 112(a), written description, rejection to the specification have been fully considered and are persuasive. The rejection of claims 21 and 63 as failing to comply with the written description requirement has been withdrawn.
Applicant’s arguments, see Response, filed 8/21/26, with respect to the 112(d) rejection have been fully considered and are persuasive. The rejection of claims 23 and 65 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 has been withdrawn.
Applicant’s arguments, see Response, filed 8/21/26, with respect to the 112(d) rejection have been fully considered and are persuasive. The rejection of claim 24 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 has been withdrawn.
Applicant’s arguments, see Response, filed 8/21/26, with respect to the obviousness-type double patenting rejection have been fully considered and are persuasive. The rejection of claims 4, 15, 19, 21-24, 61, and 63-66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-7, 10, 14-16, 24, 27-28, 48, 53-55, 80, 83, 89, 93, and 98 of copending Application No. 17/631,818 (Hirano et al. US Publication No. 2022/0291215 A1) has been withdrawn.
New Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 68-71 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 68 includes a “DP beta chain comprising (i) an amino acid selected from alanine, valine, isoleucine, methionine, phenylalanine, and tyrosine at a position corresponding to residue 112 instead of leucine of SEQ ID NO: 1; and (ii) an amino acid selected from alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine and tryptophan at a position corresponding to residue 141 instead of valine of SEQ ID NO: 1”. The interpretation of this phrase is described above in the “Sequence Interpretation” section and in the 112(b) rejection below where the DP chain has a base sequence of SEQ ID NO: 1, and requires the presence of alanine, valine, isoleucine, methionine, phenylalanine, or tyrosine at position 112 of SEQ ID NO:1 and alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine or tryptophan at position 141 of SEQ ID NO:1. However, the base sequence encompasses a number of variations including one or more substitutions and can be a fragment ranging from 29 amino acids (i.e., position 112 to position 141) up to 196 residues of SEQ ID NO: 1. As such, the base sequence of SEQ ID NO: 1 encompasses a vast array of structural modifications including substitutions, insertions, and deletions without a core structure or sequence. In addition to the broad structure encompassed by the claimed invention, a HLA class II molecule binds with an antigenic peptide in a peptide-binding groove of the molecule that is found between the alpha-1 and beta-1 domains where such binding results in the presentation of the antigenic peptide extracellularly to CD4+ cells (See instant, [0075]). The invariant residues of L112, V114, V141, L156, and M158 are located in the beta-2 domain of the beta polypeptide and are recognized and bound by CD4 T cell (See instant, [0075]). As such, the beta chain including the DP beta chain is essential for proper binding of a HLA class II molecule to an antigenic peptide, presentation of the antigenic peptide once bound to the molecule, and binding of the molecule to a CD4+ T cell. Thus, in light of the specification, the claimed HLA class II molecule comprising a DP beta chain amino acid sequence must exhibit the function of binding to an antigenic peptide, presenting the antigenic peptide extracellularly, and binding to a CD4+ T cell.
The written description requirement may be met by provided a representative number of species of the genus and/or in light of the state of the art. With regard to the state of the art, Diaz et al. teaches that molecules encoded within the class II region of the NHC are polymorphic, non-covalently associated αβ heterodimers whose function is to bind peptide antigens and display them on the cell surface for interaction with CD4+ T lymphocytes (See Diaz et al., Intl. Immunol. 15:565-576 (2003) at pg. 565, col. 1, last paragraph to col. 2, 1st paragraph) (cited in the Action mailed on 8/11/25). Characterization of MHC class II peptide binding and T cell recognition, at the molecular level, is essential to understand a central event of the immune response that could have important applications in clinical practice (See Diaz, pg. 565, col. 2, last paragraph to pg. 566, col. 1, 1st paragraph). DP is one of three isotypes of human MHC class II molecules (See Diaz, pg. 566, col. 1, 2nd paragraph). The DP isotype has been the subject of less study compared to the DR and DQ isotypes where only limited information is available on HLA-DP peptide binding and antigen-specific T cell recognition (See Diaz, pg. 566, col. 1, 3rd paragraph; pg. 573, col. 1, 2nd paragraph). Diaz et al. also teaches that little is known about the relevance of the polymorphism in the function of HLA-DP (See Diaz, pg. 566, col. 1, 3rd paragraph). Thus, Diaz sought to examine the involvement of HLA-DP polymorphism in the function of the MHC class II molecule (See Diaz, pg. 566, col. 2, 2nd paragraph; pg. 573, col. 1, 2nd paragraph). Diaz examined differences among HLA-DP alleles define 13 main polymorphic residues within the beta 1 domain: residues 8, 9, 11, 35, 36, 55, 56, 69, 76, 84, 85, 86, and 87 (See Diaz, pg. 566, col. 2, 2nd paragraph) (See also: Margolis et al., Frontiers Genet. 14:1004138 (2023) at pg. 4, col. 2, last paragraph; Table 2: identifying 14 residues (8-9, 11, 36, 55-57, 65, 69, 76, and 84-87) in the beta-1 domain to be polymorphic between different alleles) (cited in the Action mailed on 8/11/25). Six of the 13 substitutions, i.e., F9Y, G11L, F35Y, D55A, E56A, and E69K, completely abrogated recognition by the T cell clones tested thereby suggesting a crucial role for these polymorphic residues in T cell recognition of HLA-DP (See Diaz, pg. 569, col. 2, 2nd paragraph). Diaz et al. also found that substitutions at positions 84-87 demonstrated that these positions play a key role and suggest an additive effect in T cell recognition (See Diaz, pg. 569, col. 2, 2nd paragraph). Diaz et al. concluded that HLA-DP beta residues 9, 11, 35, 55, and 56 at pocket 9, residue 69 at pocket 4, and residues 84-87 in pocket 1 play a key role in T cell allorecognition (See Diaz, pg. 573, col. 1, 2nd paragraph). Moreover, Diaz et al. concluded that some mutations, i.e., residues 11 and 35, could prevent binding of the adequate peptide in the groove or change the nature of the peptide presented by affecting the conformation of the peptide presented within the antigen-binding groove of the MHC molecule (See Diaz, pg. 573, col. 2, 1st paragraph). Thus, although Diaz teaches several residues critical to a MHC class II molecule to function properly, Diaz demonstrates that even two substitutions within a specific full length DP chain allele amino acid sequence can have a serious impact on the functionality of a MHC class II molecule. Therefore, the claims are directed to MHC class II molecules comprising a DP chain amino acid sequence with a certain function but no correlated structure associated with that function. Without such structure, the specification does not convey possession of the breadth of the claimed genus.
Alternatively, the written description requirement may be met by providing a representative number of species of the genus. In this, the specification teaches a limited number of species within the claimed genus. More specifically, the specification uses the DPB1*04:01 (DP4β) gene as the base sequence (i.e., SEQ ID NO: 5 in the full length wild-type sequence and SEQ ID NO: 1 is the wild-type mature extracellular domain sequence) with random mutations at positions L112, V114, V141, L156 and M158 (See instant, Example 2, [0202]). The DPB1*04:01 (DP4β) gene with four substitutions, i.e., L112W, V114M, V141M, and M158I was expressed with the wild-type DPA1*01:03 (DPα) gene (See instant, Example 2, [0202]). This DP4 mutant exhibited enhanced binding to soluble CD4+ T cells compared to the wild-type DP4 molecules (See instant, Example 2, [0202]). Furthermore, the specification demonstrates that the L112W and V141M substitutions were critical for enhanced binding to CD4 (See instant, Example 2, [0202]; Figure 1G). The specification further demonstrates that the DP2, DP5 or DP8 sequences with the L112W and V141M substitutions resulted in enhanced binding to CD4 (See instant, Example 2, [0204]). However, the Example utilizes a full length DP beta chain with specific substitutions at specific positions. As such, the limited species in the specification do not constitute a representative number of species given the breadth of the claimed genus discussed supra. Thus, the specification is not sufficient for the skilled artisan to envisage other substitutions at other residue sites and/or fragments that would preserve function nor to envisage those substitutions other than at the specific positions with an expectation that function will be preserved.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, what is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of polypeptides which preserve the required function, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence. Therefore, claims 68-71 do not meet the written description requirement.
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 68-71 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.
It is unclear what constitutes a “DP beta chain” as set forth in the claims. Independent claim 68 recites that the beta chain requires the presence of alanine, valine, isoleucine, methionine, phenylalanine, or tyrosine at a position corresponding to residue 112 instead of leucine of SEQ ID NO: 1, and alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine or tryptophan of SEQ ID NO: 1. However, the scope of claim 68 encompasses multiple interpretations with respect to what constitutes the DP beta chain. The first interpretation encompasses where the DP beta chain comprises SEQ ID NO: 1 where the residue at position 112 is alanine, valine, isoleucine, methionine, phenylalanine, or tyrosine, and the residue at position 141 is alanine, isoleucine, leucine, methionine, phenylalanine, tyrosine or tryptophan. As such, this first interpretation requires 100% identity to SEQ ID NO: 1 as the base sequence with the two specific substitutions, but would exclude additional substitutions, deletions and/or insertions and exclude fragments. The second interpretation encompasses where the DP beta chain comprises any amino acid sequence as a base sequence as long as the sequence contains the specific substitutions at the positions corresponding to 112 and 141. Such interpretation is supported by the claim language, i.e., an amino acid selected from…. at a position corresponding to amino acid residue 112 or 141 of SEQ ID NO: 1. Corresponding to a specific residue at a specific position would imply that the base sequence is not SEQ ID NO: 1. Furthermore, the specification at paragraph [0109], [0111] indicates that the insertion of multiple amino acids at a single position of SEQ ID NO:1 is embraced by the DP beta chain recited in the claims; the specification at paragraph [0112] indicates that a DP beta chain comprises more than one substitution mutation relative to the wild-type DP chain; and the specification at paragraph [0146] indicates that fragments of the beta chain, including the transmembrane domain of the beta chain, can be deleted from SEQ ID NO: 1.
Given all these variations to the sequence of SEQ ID NO: 1 and given that the scope of claim 68 encompasses multiple interpretations, it is unclear what degree of sequence and/or functional similarity a polypeptide must have with the beta chain of SEQ ID NO:1 in order for the polypeptide to be considered a “DP beta chain”. The claims do not particularly point out the limits of the HLA class II molecule comprising a DP beta chain embraced within the scope of the claims.
Please note that given the variability taught in the specification including one or more mutations and fragments, the Examiner is interpreting that the scope of DP beta chain encompasses the first interpretation, i.e., comprising SEQ ID NO: 1 with the two specific substitutions required, in order to advance prosecution. Also please note that claims 69-71 are rejected by virtue of their dependency.
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 68-69 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. Based upon an analysis with respect to the claims as a whole, claims 68-69 do not recite something significantly different than a judicial exception.
Analysis:
Step 1: Is the claimed invention directed to a process, machine, manufacture, or composition of matter? Yes, claims 68-69 are directed to a composition of matter.
Step 2A: Prong One: Do the claims recite an abstract idea, law of nature, or natural phenomenon? The claims at issue recite a nature-based product limitation. In particular, claims 68-69 recite a polypeptide which can be naturally occurring DP beta 1 chain HLA class II histocompatibility antigen present in Panthera leo (See GenBank Accession number XP_042793382 (HLA class II histocompatibility antigen, DP beta 1 chain [Panthera leo], 11 August 2021). The comparison between the DP beta 1 chain in Panthera leo and instant SEQ ID NO: 1 is as follows:
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Notably, it contains a Met at the position corresponding to position 112 of SEQ ID NO: 1 and a Leu at the position corresponding to position 141 of SEQ ID NO: 1. As such, the DP beta 1 chain in Panthera leo constitutes a DP beta chain comprising an amino acid of methionine at the position corresponding to 112 of SEQ ID NO: 1 and an amino acid of leucine at the position corresponding to position 141 of SEQ ID NO: 1 as recited in instant claim 68. Moreover, it is noted that the instant specification defines a HLA class II molecule where a typical MHC Class II molecule comprises two protein chains: an alpha chain and a beta chain (See instant [0072]). These two chains fold to allow binding to an antigenic peptide and then to a CD4+ T cell (See instant [0075]). As such, a HLA Class II molecule in Panthera leo would similarly contain both chains naturally without evidence to the contrary. The markedly different characteristics analysis is used to determine if this nature-based product constitutes one of the judicially recognized exceptions. There is no evidence of record that the polypeptides embraced by instant claims have any difference in function, structure, or other properties compared to the naturally occurring polypeptide. As such, the claimed MCH class II molecule comprising a DP beta chain and a DP alpha chain are not markedly different when compared to their naturally occurring counterparts. Accordingly, the claims at issue recite a judicially recognized “product of nature” exception.
Prong Two: Do the claims recite additional elements that integrate the judicial exception into a practical application? Claims 68-69 do not recite any additional elements. The limitations of claims 68-69 thus fail meaningfully to limit the claims because it is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, the claim limitations do not integrate the judicial exception into a practical application and the claims are therefore directed to the judicial exception.
Step 2B: Do the claims recite additional elements that amount to significantly more than the judicial exception? Claims 68-69 do not recite any additional elements. Accordingly, claims 68-69 do not qualify as eligible subject matter.
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 68-69 are rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. US Publication No. 2018/0244759 A1 published on August 30, 2018 (cited in the Action mailed on 8/11/25) in view of UniProt Accession No. P04440, DPB1_Human, (first available 1987) (cited in the Action mailed on 8/11/25), and UniProt Accession No. P04440, DPB1_Human, variant viewer (P04440 first available 1987, variant viewer for V170M last updated 2015) (cited in the Action mailed on 8/11/25), alone or as evidenced by UniProt Accession No. A0A0D6K9C3, MHC class II antigen, DPB1 (2015) (cited in the Action mailed on 8/11/25).
For claims 68-69, Anderson et al. teaches a method of generating an immune response including enhancing the generation of antibodies by using a protein’s “peptidogenic potential” via altering the conformational dynamics of a starting protein while maintaining that protein’s 3D conformation (See Anderson, [0032]). These peptidogenic proteins can then be used to mount an immune response, used as a vaccine and/or generate antibodies (See Anderson, [0032]). Furthermore, Anderson et al. defines “peptidogenicity” as referring to the propensity of a protein to efficiently yield a robust set of diverse peptides which can be used to yield an immune response (See Anderson, [0041]). A “peptidogenic protein” refers to a mutated protein that has been modified in its amino acid sequence to alter its conformational dynamics as compared to the starting protein sequence while maintaining a similar conformation to the starting protein (See Anderson, [0042]).
Anderson et al. teaches in Table 5, SEQ ID NO: 185, which is human HLA class II histocompatibility antigen, DP beta 1 chain as a specific protein target (See Anderson, Table 5, SEQ ID NO: 185) thereby constituting an HLA class II molecule comprising a DP beta chain as recited in instant claim 68 where the DP beta chain is DP1 as recited in instant claim 69. Anderson’s SEQ ID NO: 185 encompasses up to 30 amino acids that can be substituted (See Anderson, Table 5, SEQ ID NO: 185). One of the exemplified sites of mutation to generate peptidogenic proteins is L141 (See Anderson, Table 5, SEQ ID NO: 185). It is noted that L141 corresponds to instant position L112 when the signal peptide is included in the amino acid sequence. Anderson et al. teaches that L141 can be substituted with Ala, Val, Gly or Ile (See Anderson, Table 5, SEQ ID NO: 185) thereby constituting where the amino acid is Ala, Val or Ile at a position corresponding to amino acid residue 112 of SEQ ID NO: 1 as recited in instant claim 68.
Regarding where instant position 141 is an amino acid residue other than valine such as Met, Anderson et al. teaches that the base human HLA class II histocompatibility antigen, DP beta 1 chain has an amino acid sequence depicted in UniProt ID No. P04440 (See Anderson, Table 5, SEQ ID NO: 185). UniProt P04440 depicts the naturally occurring human BP beta 1 chain (See UniProt P04440, pg. 12). As such, when combining the natural human BP beta 1 chain with Anderson’s SEQ ID NO: 185, an amino acid sequence comprising L112A/V/I is encompassed. UniProt P04440 also identifies 362 variants of the naturally occurring human BP beta 1 chain including V170M (See UniProt P04440, variant viewer, pg. 14). The human MHC class II antigen, BP beta 1 chain amino acid sequence with a V170M substitution is evidenced by UniProt A0A0D6K9C3. It is noted that V170 corresponds to instant position V141 when the signal peptide is included in the amino acid sequence. As such, a V141M substitution constitutes where the amino acid is Met at a position corresponding to amino acid residue at position 141 of SEQ ID NO: 1 as recited in instant claim 68.
Therefore, in light of the breadth of the DP beta chain of instant claims 68-69, and since Anderson refers to UniProt P04440 as the base sequence, which identifies variants of the base sequence including V141M, an ordinary skilled artisan would be motivated with a reasonable expectation of success before the effective filing date of the present application to modify Anderson’s SEQ ID NO: 185 by substituting the naturally occurring P04440 DP beta 1 chain amino acid sequence at L112 with Ala, Val or Ile and V141 with Met alone or in combination with up to an additional 58 substitutions including those of Anderson’s SEQ ID NO: 185 in order to improve peptidogenicity of the natural HLA class II histocompatibility antigen and generate antibodies against the DP beta 1 chain because a L112A/V/I substitution was known to improve peptidogenicity of the HLA class II histocompatibility antigen as taught by Anderson and because a V141M substitution was known to result in a deleterious variation as taught by UniProt P04440, variant viewer. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, as evidenced by the references, especially in the absence of evidence to the contrary.
Thus, the invention as a whole is prima facie obvious over the references, especially in the absence of evidence to the contrary.
Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Anderson et al. US Publication No. 2018/0244759 A1 published on August 30, 2018 (cited in the Action mailed on 8/11/25) in view of UniProt Accession No. P04440, DPB1_Human, (first available 1987) (cited in the Action mailed on 8/11/25), UniProt Accession No. P04440, DPB1_Human, variant viewer (P04440 first available 1987, variant viewer for V170M last updated 2015) (cited in the Action mailed on 8/11/25), alone or as evidenced by UniProt Accession No. A0A0D6K9C3, MHC class II antigen, DPB1 (2015) (cited in the Action mailed on 8/11/25), and further in view of UniProt Accession No. P20036, DPA1_Human, (first available 1991) (cited in the Action mailed on 8/11/25), and Cruz-Tapias et al., Major histocompatibility complex: Antigen processing and presentation. In: Anaya JM, Shoenfeld Y, Rojas-Villarraga A, et al., editors. Autoimmunity: From Bench to Bedside [Internet]. Bogota (Colombia): El Rosario University Press; 2013 Jul 18. Chapter 10. Available from: https://www.ncbi.nlm.nih.gov/books/NBK459467/ (cited in the Action mailed on 8/11/25).
For claim 70, with respect to the incorporated limitations from claim 68, please see discussion of Anderson, UniProt P04440 along with the variant viewer supra.
For claim 70, as discussed supra for claim 68, Anderson et al. teaches a method of generating an immune response including enhancing the generation of antibodies by using a protein’s “peptidogenic potential” via altering the conformational dynamics of a starting protein while maintaining that protein’s 3D conformation (See Anderson, [0032]). These peptidogenic proteins can then be used to mount an immune response, used as a vaccine and/or generate antibodies (See Anderson, [0032]). “Cocktails” of the peptidogenic proteins comprising a mixture of different peptidogenic proteins derived from different starting materials can be used to induce an immune response (See Anderson, [0113]). Anderson et al. teaches in Table 5 proteins containing one or more mutations that improve peptidogenicity to be used as targets to generate antibodies (See Anderson, [0150]). Table 5 lists SEQ ID NO: 185, which is human HLA class II histocompatibility antigen, DP beta 1 chain as a specific protein target, and SEQ ID NO: 377, which is a human HLA class II histocompatibility antigen, DP alpha 1 chain with up to 21 identified positions that can be mutated (See Anderson, Table 5, SEQ ID NO: 377). The base human HLA class II histocompatibility antigen, DP alpha 1 chain has an amino acid sequence depicted in UniProt ID No. P20036 (See Anderson, Table 5, SEQ ID NO: 377). UniProt P20036 depicts the naturally occurring human BP alpha 1 chain (See UniProt P20036, pg. 9). When comparing the naturally occurring HLA class II histocompatibility antigen, DP beta 1 chain amino acid sequence with instant SEQ ID NO: 6, there is 100% identity. As such, when the target protein is a human HLA class II histocompatibility antigen, DP beta 1 chain of SEQ ID NO: 377 that can be mutated, the DP alpha 1 chain has an amino acid sequence that is identical to instant SEQ ID NO: 6 in light of the “Sequence Interpretation” section supra for claim 70.
However, Anderson et al. does not expressly teach that the target protein in need of improved peptidogenicity is a HLA class II molecule comprising the DP beta chain of claim 68 and the DP alpha chain of claim 70, i.e., that the two chains are complexed together.
Cruz-Tapias et al. teaches that HLA class II molecules are composed of two non-covalently associated polypeptide chains; namely, an alpha and a beta chain (See Cruz-Tapias, pg. 5, last paragraph). A peptide binding groove is formed between the alpha-1 and beta-1 domains in order to allow the HLA class II molecule to bind to antigenic peptides (See Cruz-Tapias, pg. 6, 2nd paragraph). The HLA class II molecule bound to an antigenic peptide then presents the antigenic peptide in a conformation that allows the antigenic peptide to be bound to a CD4+ T cell (See Cruz-Tapias, pg. 6, 2nd paragraph). As such, both the alpha and beta chains are necessary for HLA class II molecules to function properly.
Therefore, an ordinary skilled artisan would be motivated with a reasonable expectation of success before the effective filing date of the present application to modify a cocktail of peptidogenic proteins derived from different starting materials such that the cocktail comprises at least SEQ ID NO: 185 (i.e., DP beta 1 chain) having a L112A/V/I substitution and a V141M substitution as discussed supra associated non-covalently to SEQ ID NO: 377 (i.e., DP alpha 1 chain) having an amino acid sequence of instant SEQ ID NO: 6 thereby forming an HLA class II molecule in order to improve peptidogenicity of the HLA class II molecule and generate antibodies against it because HLA class II molecules were known to require the DP alpha 1 and beta 1 chains in order to form the proper antigen binding groove conformation, and thus, selecting to include both the DP alpha 1 chain and beta 1 chain proteins together in the same cocktail would be advantageous to improve peptidogenicity and generate antibodies or an immune response. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application, as evidenced by the references, especially in the absence of evidence to the contrary.
Allowable Subject Matter
Claims 4, 15, 19, 22, 24, 61, and 66 are allowed. As stated in the Action mailed on 3/19/26, claims 4, 15, 19, 22, 24, 61, and 66 are free of the prior art as there is no teaching or suggestion for a DP beta chain comprising 100% identity with any N- and/or C-terminal additions to SEQ ID NO: 3. The closest prior art is Anderson et al. US Publication No. 2018/0244759 A1 published on August 30, 2018 (cited in the Action mailed on 8/11/25). Anderson et al. teaches a method of generating an immune response including enhancing the generation of antibodies by using a protein’s “peptidogenic potential” via altering the conformational dynamics of a starting protein while maintaining that protein’s 3D conformation (See Anderson, [0032]). A “peptidogenic protein” refers to a mutated protein that has been modified in its amino acid sequence to alter its conformational dynamics as compared to the starting protein sequence while maintaining a similar conformation to the starting protein (See Anderson, [0042]). An exemplary peptidogenic protein includes SEQ ID NO: 185, which is human HLA class II histocompatibility antigen, DP beta 1 chain as a specific protein target (See Anderson, Table 5, SEQ ID NO: 185). Anderson’s SEQ ID NO: 185 encompasses up to 30 amino acids that can be substituted (See Anderson, Table 5, SEQ ID NO: 185). One of the exemplified sites of mutation to generate peptidogenic proteins is L141 (See Anderson, Table 5, SEQ ID NO: 185). It is noted that L141 corresponds to instant position L112 when the signal peptide is included in the amino acid sequence. Anderson et al. teaches that L141 can be substituted with Ala, Val, Gly or Ile (See Anderson, Table 5, SEQ ID NO: 185). However, Anderson does not teach or suggest where instant L112 is substituted to L112W or where instant V141 is substituted to V141M. Thus, claims 4, 15, 19, 22, 24, 61, and 66 are novel and nonobvious.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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