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. Election/Restriction: Applicant's election of Group I (claims 1, 4-5, 10-14, 16, 18, 22-24, 26-30, 34-36 and 40 ; species : Type 2 Diabetes ), filed on 12 / 15 /202 6 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). In response to an interview with the Examiner on 1 / 29 /2026, Attorney Joseph W. Ricigliano filed an amendment on 2 / 9 /2026. Amended claims 42 , 53, 61, ( 2 / 9 /2026) , and previous l y presented claims 43-52, 54-60, 62, are pending and under consideration by the Examiner. Claims 1-41 have been canceled. Information Disclosure Statement 3. The information disclosure statement (IDS) submitted on 5 / 16 /202 5 is in compliance with the provisions of 37 CFR 1.97 and ha s been considered by the examiner. Applicant is reminded of their duty to disclose to the Office all information known to the person to be material to patentability as defined in 37 CFR 1.56. As stated therein, “[e]ach individual associated with the filing and prosecution of a patent application has a duty of candor and good faith in dealing with the Office, which includes a duty to disclose to the Office all information known to that individual to be material to patentability as defined in this section”. Claim Rejections - 35 USC § 112 (a), written description 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. 4a. Claims 42-62 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 claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. The instant claims are drawn to a method of increasing the number of CD4 + T cells that express FOXP3 in an individual in need of treatment for a disease or disorder, the method comprising administering to the individual an effective amount of a heterodimer comprising a first polypeptide and a second polypeptide, wherein: (i) the first polypeptide comprises, in the N-terminal to C-terminal direction, a) a scaffold polypeptide sequence comprising an interspecific dimerization sequence and having at least 95% sequence identity to at least 175 contiguous amino acids of an IgG1 sequence selected from SEQ ID NOs:71 to 76, b) a masking polypeptide sequence comprising a TGF-β receptor polypeptide sequence having at least 95% sequence identity to QLCKF CDVRFSTCDN QKSCMSNCSI TSICEKPQEV CVAVWRKNDE NITLETVCHD PKLPYHDFIL EDAASPKCIM KEKKKPGETF FMCSCSSDEC NDNIIFSEE (SEQ ID NO: 122), and c) optionally, an independently selected linker polypeptide sequence comprising from 1 to 25 amino acids interposed between the scaffold polypeptide sequence and the masking polypeptide sequence of the first polypeptide; and (ii) the second polypeptide comprises, in the N-terminal to C-terminal direction, a) an IL-2 immunomodulatory polypeptide sequence having at least 95% sequence identity to 120 contiguous amino acids of SEQ ID NO:9, b) a scaffold polypeptide sequence comprising a counterpart interspecific dimerization sequence to the interspecific dimerization sequence in the first polypeptide and having at least 95 % sequence identity to at least 175 contiguous amino acids of an IgG1 sequence selected from SEQ ID NOs:71 to 76, c) a TGF- β3 polypeptide sequence having at least 95% sequence identity to at least 100 contiguous amino acids of SEQ ID NO:111, and (d) optionally, independently selected linker polypeptide sequences comprising from 1 to 25 amino acids interposed (A) between the IL-2 immunomodulatory polypeptide sequence and the scaffold polypeptide sequence of the second polypeptide, and/or (B) between the scaffold polypeptide sequence and the TGF- β3 polypeptide sequence of the second polypeptide; wherein the TGF- β receptor polypeptide sequence and the TGF- β 3 polypeptide sequence interact with each other to reversibly mask the TGF- β 3 polypeptide sequence, the interspecific dimerization sequence and the counterpart interspecific dimerization sequence interact with each other to form the heterodimer, and the disease or disorder is selected from familial hypercholesterolemia, Gaucher disease, Hunter syndrome, Krabbe disease, maple syrup urine disease, metachromatic leukodystrophy, cystic fibrosis, mitochondrial encephalopathy, lactic acidosis, stroke- like episodes (MELAS), Niemann-Pick disease, phenylketonuria (PKU), porphyria , sickle cell anemia, Tay-Sachs disease, Wilson's disease, insulin resistant type 2 diabetes (T2D), insulin deficient T2D, pre-T2D, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). The specification on pages 163-167, Examples 3 -6, discloses : Experiment 3: Induction of Foxp3+ expression from human peripheral CD4+ T cells by PSM- 4033-4039 ; Experiment 4: Induction of Foxp3+ iTregs by PSM-4033-4039 from CD4+ T cells activated by an allogeneic lymphocyte reaction ; Experiment 5: PK experiment in mice using PSM-4033-4039 ; and Experiment 6: Induction of FoxP3 by PSM-4033-4039, in which the masked TGF-β construct PSM-4033-4039 was used (sequence of construct 4033 is provided in FIG. 1 0 B (SEQ ID NO:191), and the sequence of construct 4039 is provided in FIG. 1 0 C (SEQ ID NO: 192) ) in all the above experiments . The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention.” The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus. The claims encompass an enormous genus of heterodimers of undefined structure and length that have the function of increasing the number of CD4 + T cells that express FOXP3. As a result, there are potentially thousands of heterodimer p olypeptide sequences that could be made and still fall within the scope of the claims , due to the recitation of the limitation “95% sequence identity to at least 175 contiguous amino acids of SEQ ID NO:71 to 76”, “95% sequence identity to at least 120 contiguous amino acids of SEQ ID NO:9”, and “95% sequence identity to at least 100 contiguous amino acids of SEQ ID NO:111 ” . This represents a large pool of potential poly peptides that have the required function of increasing the number of CD4 T cells that express FOXP3 . he claims as recited would represent a large pool of variant peptides that must have similar functional activity. A 95% variance, for example, in the polypeptide set forth in SEQ ID NO: 7 1 that is 227 amino acids in length translates into 5% of the amino acid residues that may be added, deleted, substituted, or otherwise mutated anywhere throughout the entire length of the 227 residue amino acid polypeptide. Moreover, there is no limitation stating that the substitution, for example, be a conservative substitution. As a result, there are potentially thousands of variant permutations that could be made in the claimed heterodimer . Applicants have not described which portions of SEQ ID NO: 7 1 , for example, are critical to the function of the protein. The specification provides limited guidance regarding which amino acids can be modified in the genus of poly peptides, while maintaining any given function. Therefore, these structures (i.e., sequence variants) are claimed only by their functional characteristics and the specification fails to provide sufficient correlation between the claimed functional characteristics and the necessary structural components (i.e., critical domains within the sequences). Thus, the genus of claimed first and second peptides is extremely broad because the claims recite incompletely described poly peptides. One of ordinary skill in the art would not be reasonably apprised of the structure of the claimed poly peptides without an adequate description of its component parts or overall makeup. The claims as recited do not impart enough structural information to permit one of ordinary skill in the art to reasonably recognize or understand that Applicant was in possession of the full scope of the genus of variant poly peptides recited in the claims. The invention contemplates poly peptide variants , characterized by having at least 95% sequence identity to at least 100 contiguous amino acids of any of the recited s equences , with mutations as recited in claim 42 . T he specification does not provide adequate written description to identify the broad and variable genus of poly peptides because, inter alia , the specification does not disclose a correlation between the necessary structure of the poly peptide and the function(s) of the poly peptide ; and thus, the specification does not distinguish the claimed genus from others. Accordingly, the specification does not define any structural features commonly possessed by members of the genus of variant poly peptides. In addition, because the genus of claimed polypeptide s is highly variable (i.e. , each variant first and second poly peptide in the heterodimer would necessarily have a unique structure; see MPEP 2434), the generic description of the variant poly peptide s is insufficient to describe the genus. Further, A pplicants have not shown possession of a representative number of species of the claimed poly peptides. As noted above, the claims are generic for the components of the peptide. The disclosure of only a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem , 323 F.3d at 966, 63 USPQ2d at 1615; Noelle v. Lederman , 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.") (MPEP 2163). Vas-Cath Inc. v. Mahurkar , 19 USPQ2d 1111, makes clear that "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, whatever 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.) Protein chemistry is probably one of the most unpredictable areas of biotechnology. Consequently, the effects of sequence dissimilarities upon protein structure and function cannot be predicted. Bowie et al. (Science, 1990, 247:1306-1310) teach that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique three-dimensional structures that allows them to function and carry out the instructions of the genome and further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex (column 1, page 1306). Bowie et al. further teach that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the three - dimensional structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all (column 2, page 1306). The sensitivity of proteins to alterations of even a single amino acid in a sequence are exemplified by Burgess et al. (J. Cell Biol. 111:2129-2138, 1990) who teach that replacement of a single lysine reside at position 118 of acidic fibroblast growth factor by glutamic acid led to the substantial loss of heparin binding, receptor binding and biological activity of the protein and by Lazar et al. (Mol. Cell. Biol., 8:1247-1252, 1988) who teach that in transforming growth factor alpha, replacement of aspartic acid at position 47 with alanine or asparagine did not affect biological activity while replacement with serine or glutamic acid sharply reduced the biological activity of the mitogen. These references demonstrate that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein. Additionally, Bork (Genome Research, 2000, 10:398-400) clearly teaches the pitfalls associated with comparative sequence analysis for predicting protein function because of the known error margins for high-throughput computational methods. Bork specifically teaches that computational sequence analysis is far from perfect, despite the fact that sequencing itself is highly automated and accurate (p age 398, column 1). One of the reasons for the inaccuracy is that the quality of data in public sequence databases is still insufficient. This is particularly true for data on protein function. Protein function is context dependent, and both molecular and cellular aspects have to be considered (p age 398, column 2). Conclusions from the comparison analysis are often stretched with regard to protein products (p age 398, column 3). Further, although gene annotation via sequence database searches is already a routine job, even here the error rate is considerable (p age 399, column 2). Most features predicted with an accuracy of greater than 70% are of structural nature and, at best, only indirectly imply a certain functionality (see legend for table 1, page 399). As more sequences are added and as errors accumulate and propagate it becomes more difficult to infer correct function from the many possibilities revealed by database search (p age 399, paragraph bridging columns 2 and 3). The reference finally cautions that although the current methods seem to capture important features and explain general trends, 30% of those features are missing or predicted wrongly. This has to be kept in mind when processing the results further (p age 400, paragraph bridging cols 1 and 2). The state of the art regarding the structure-function correlation cannot be relied upon because functional characteristics of any peptide/protein are determined by its structure as evidenced by Greenspan et al. 1999 (Defining epitopes: It's not as easy as it seems; Nature Biotechnology, 17:936-937). Greenspan et al. teach that as little as one substitution of an amino acid (e.g. , alanine) in a sequence results in unpredictable changes in the 3-dimenstional structure of the new peptide sequence which, in turn, results in changes in the functional activity such as binding affinity of the peptide sequence (page 936, 1st column). Greenspan et al. teach that contribution of each residue (i.e. , each amino acid) cannot be estimated with any confidence if the replacement affects the properties of the free form of the molecule (page 936, 3rd column). Given not only the teachings of Bowie et al., Lazar et al., Burgess et al., and Greenspan et al., but also the limitations and pitfalls of using computational sequence analysis and the unknown effects of alternative splicing, post translational modification and cellular context on protein function as taught by Bork, the claimed poly peptides could not be predicted as claimed. Applicant has provided little descriptive support beyond the mere presentation of generic or partially named structures to enable one of ordinary skill in the art to determine the actual structural composition of the claimed genus of first and second poly peptides in the heterodimer to be administered in the claimed method . Although the prior art outlines art-recognized procedures for producing and screening for recombinant proteins this is not sufficient to impart possession of the genera of variant p roteins to Applicant. Even though a few structurally identifiable composition components were described in the specification, they may not be sufficient, as the ordinary artisan would not necessarily immediately recognize how to put them together in such a way as to form completely constructed first and second poly peptide s such that one would be able to distinguish it from the poly peptides of the prior art. Without an adequate structural description of the claimed components and descriptive support on how to put them together, one of ordinary skill in the art would not be reasonably apprised that Applicant was in possession of the genus of first and second polypeptides to be administered in the claimed method . While "examples explicitly covering the full scope of the claim language" typically will not be required, a sufficient number of representative species must be included to "demonstrate that the patentee possessed the full scope of the [claimed] invention." Lizard tech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1345, 76 USPQ2d 1724,1732 (Fed. Cir. 2005). In the absence of sufficient recitation of distinguishing characteristics, the specification does not provide adequate written description of the claimed genus of polypeptides . One of skill in the art would not recognize from the disclosure that the A pplicant was in possession of the claimed method. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features (see, Univ. of Rochester v. G.D. Searle& Co ., 358 F.3d 916,927, 69 USPQ2d 1886, 1895 (Fed. Cir. 2004); accord Ex Parte Kubin , 2007-0819, BPAI 31 May 2007, opinion at p. 16, paragraph 1). 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). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115). Therefore , the full breadth of the claims fails to meet the written description provision of 35 U.S.C. §112, first paragraph. In the instant case, Applicants have failed to describe , for example, which “ amino acid sequences having at least 95% sequence identity to 175 contiguous amino acids of SEQ ID NO:71 to 76 ” in the first and second polypeptide in the heterodimer to be administered in the claimed method, ha ve the desired properties claimed. Claim Rejections - 35 USC § 112(b) 5 . 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. 5 a. Claims 4 2-62 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 pre-AIA the applicant regards as the invention. Claim 4 2 is rejected as vague and indefinite for several reasons. Claim 4 2 , line 2, is vague and indefinite because it recites “CD4 T cells” rather than the correct “ CD4+ T cells ” (See specification, page 9, [0035]). Claim 42, line 41, recites “insulin resistant type 2 diabetes (T2D)” while claim 53, and 62 recite “insulin resistance T2D” and it is unclear why there are two different recitations in the claims. It is suggested that the same term be recited in the all the claims for consistency. Claim 43, line 2, is vague and indefinite because it recites “a substitution” in the scaffold polypeptide and it is unclear what the substitution is and in which scaffold polypeptide because claim 42 recites that the scaffold polypeptide is selected from SEQ ID NO:71 to 76. Claim 47 is vague and indefinite because it recites “t he IL-2 immunomodulatory polypeptide sequence comprises an F42A, F42T, H16A, or H16T substitution” but fails to recite “in SEQ ID NO:9”. Furthermore, claim 47 should correctly depend from claim 46. Claim 48, lines 2-3, is vague and indefinite because it recites “… a substitution of any one, any two, any three, any four, or all five of amino acids F30, D32, 552, E55, and D118” which would be the substitutions in SEQ ID NO:122, however, there is no F30, D32, 552, E55, and D118 in SEQ ID NO:122. Instead in SEQ ID NO:122 there is E30, P32, V52, D55 . Furthermore, SEQ ID NO:122 is only 104 amino acids. Similarly, claim 49 is vague and indefinite for the recitation of “a substitution of any one, any two, any three, any four, or all five of amino acids F30, D32, 552, E55, and D118”, for the reasons set forth above for claim 48. Similarly, claim 50 is vague and indefinite because there are only 104 amino acids in SEQ ID NO:122, and the absence of a D118A substitution. Claim 51 is vague and indefinite because it fails to recite “C77S substitution in SEQ ID NO:111”. Similarly, claim 52 is vague and indefinite because it fails to recite “C77S substitution in SEQ ID NO:111”. Claim 53, line 6, is vague and indefinite for the recitation of “one or more doses”, and there is no upper limit on the number of doses. Furthermore, the claim is unclear with respect to the times and interval of dosage to be administered because the toxicity of cytokines can be significant even in microgram amounts. Similarly, claim 54-60, are vague and indefinite for the recitation of “one or more doses”, and the claims do not recite the intervals of dosage. Claim 56, lines 1-2, is vague and indefinite for the recitation of “consists essentially of a first polypeptide” and it is unclear what t he metes and bounds of the term “essentially” are. It is suggested that this term be deleted from the claim to obviate this rejection. Claims 44-46, and 61 , are rejected as vague and indefinite insofar as they depend on the above rejected claims for their limitations. Conclusion No claim is allowed. Claims 42-62 are rejected. Advisory Information Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Value for firstName-middleName-lastName?" \* MERGEFORMAT PREMA MARIA MERTZ whose telephone number is FILLIN "Insert your individual area code and phone number." \* MERGEFORMAT (571)272-0876 . 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Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form. /PREMA M MERTZ/ Primary Examiner, Art Unit 1646 /VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674