CTNF 18/252,081 CTNF 95754 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia 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 Claims 2, 6-8, 11-14, 16-18, 23-26 and 31 are pending and under consideration. It is noted that prior art does not teach or suggest an anti-MAdCAM comprising a heavy chain variable region and a light chain variable region wherein the heavy chain variable region comprises wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1445, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1367. However, the claims are not limited to the anti-MAdCAM antibody, but also include 1) antibody variants as evidenced by claims 6 and 7; 2) antibody-effector conjugates, as evidenced by claims 17 and 18; 3) a method of treating a subject with inflammatory bowel disease; 4) a method of treating a subject with an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, or a GVHD; 5) a method of preventing an autoimmune disorder in a subject at risk for having the autoimmune disorder. As shown below, the specification lacks written description support and/or enablement for the claims. Priority It is acknowledged that this application is a national phase of International Application No. PCT/US2021/059846, filed November 18, 2021, which claims priority to U.S. Provisional Patent Appl. No. 63/115,235, filed November 18, 2020; U.S. Provisional Patent Appl. No. 63/115,243, filed November 18, 2020; U.S. Provisional Patent Appl. No. 63/117,914, filed November 24, 2020; and U.S. Provisional Patent Appl. No. 63/117,918, filed November 24, 2020. The priority date has been established as November 18, 2020. Information Disclosure Statement The Information Disclosure Statements filed on 08/21/2023 and 11/13/2024 have been considered and entered by examiner. Claim Rejections - 35 USC § 112 07-36 AIA The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claim 6 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 6, which depends on claim 2, recites “wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1445, 1477 , or 1480 ”. However, SEQ ID NO: 1477 or 1480 does not comprise HCDRs 1-3 of SEQ ID NOs: 1499-1506-1507. The alignments of SEQ ID NO: 1477 and 1480 with HCDRS are shown below: Sequence 1477, US/18252081 Query Match 86.7%; Score 186.3; Length 119; Best Local Similarity 42.2%; Matches 35; Conservative 1; Mismatches 0; Indels 47; Gaps 2; Qy 1 FTFSSYWMH-------------SYISGSGGYTNYA------------------------- 22 ||||||||| ||||||||||||| Db 27 FTFSSYWMHWVRQAPGKGLEWVSYISGSGGYTNYADSVKGRFTISRDNSKNTLYLQMNSL 86 Qy 23 ---------CARDRPYYYDMDVW 36 ||||||||||:||| Db 87 RAEDTAVYYCARDRPYYYDIDVW 109 Sequence 1480, US/18252081 Query Match 87.1%; Score 187.3; Length 119; Best Local Similarity 42.2%; Matches 35; Conservative 1; Mismatches 0; Indels 47; Gaps 2; Qy 1 FTFSSYWMH-------------SYISGSGGYTNYA------------------------- 22 ||||||||| ||||||||||||| Db 27 FTFSSYWMHWVRQAPGKGLEWVSYISGSGGYTNYADSVKGRFTISRDNSKNTLYLQMNSL 86 Qy 23 ---------CARDRPYYYDMDVW 36 ||||||||||:||| Db 87 RAEDTAVYYCARDRPYYYDLDVW 109 Thus, claim 6 fails to include all the limitations of claim 2. Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements. Claim Rejections - 35 USC § 112 07-30-01 AIA 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. 07-31-01 Claims 2, 6-8, 11-14, 16-18, 23-26 and 31 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 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. This is a WRITTEN DESCRIPTION rejection . The claims are drawn to a broad genus antibody or antigen binding fragment thereof. By reciting “wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO:1445, 1477 or 1480 and the light chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1367” (see claim 7), which would allow up to 10 amino acids changes (such as insertions, deletions, substitutions, or combination thereof). Given Broadest Reasonable Interpretation (BRI), the claims encompass billions of possible variants of SEQ ID NO: 1445 or SEQ ID NO: 1367. The claims also encompass a broad genus of antibody-effector conjugates, as evidenced by claims 17 and 18. Claim 17 recites the antibody or antigen binding fragment is “linked or associated with an effector molecule ”. The specification does not limit the term “effector molecule”. Given BRI, “effector molecule” encompasses at least all possible Immune Cell Inhibitory Molecule (ICIM) binding/modulating moieties, Inhibitory Immune Checkpoint (IIC) binding/modulating moieties, Immune Cell Stimulatory Molecule (ICSM) binding/modulating moieties (see paragraphs [0105-0107] of the instant publication US 2024/0010722 A1). Thus, “effector molecule”, which is defined by functions only, would encompass small molecule, peptide, protein, antibody, oligonucleotide, or siRNA, etc… binding to different targets (e.g. targets listed in Table 1 of specification). These effector molecules vary significantly, have different structures and physical/chemical properties, and function through different mechanisms. Claim 18 recites “wherein the effector molecule is a PD-1 agonist antibody ”, given BRI, the claim would encompass all possible PD-1 agonist antibodies (known or yet to be discovered). In addition, as evidenced by claim 16, the claims encompass the antibodies or antigen binding fragment bind to antigens other than MAdCAM. The specification discloses only one antibody which read on the instant claim 2, which binds to MAdCAM and comprises the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1445, and wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1367, and only two types of antibody-effector molecule conjugates 1) MAdCAM antibody-IL2 conjugates: MIAB212, MIAB218, MIAB224, MIAB230 (see Table 11); and 2) MAdCAM antibody-anti-PD-1 conjugates: PMAB16, PMAB18, PMAB66, and PMAB67 (see Table 12). In addition, the specification does not disclose any data related to the therapeutic activity of MIAB212, MIAB218, MIAB224, or MIAB230. The specification shows that PMAB18 downregulates CCL4, IL-17A, CXCL10, and IFNG in small intestine (Example 42). The specification alleges that PMAB58 improves survival time in GVHD (Example 41), however, no data are disclosed to support the conclusion. Taken together, thus, the specification provides insufficient written description to support the genus encompassed by the claims. Vas-Gath, Inc. v" Mahurkar , 19 USPQ2d 1111, makes clear that "to satisfy the written description requirement, an 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, and that the invention, in that context, is whatever is now claimed". Regarding up to 10% variation to SEQ ID NO: 1445 or SEQ ID NO: 1367, although the claims recite HCDRs 1-3 and LCDRs 1-3 for the antibody or antigen-binding fragment thereof, it is well known that in the variable domain of an antibody, even outside the CDRs, can significantly impact antibody binding. Mutations in the framework regions (non-CDR areas) can alter the structure and dynamics of the antibody, affecting its ability to bind to its target antigen. For example, even single amino acid change in antigen-distal framework position can result in different conformational space and potentially different binding functions, see § Significance on page E486 of Koenig (Koenig et al., PNAS, E486-E495, Publication Date: 01/05/2017). Regarding claimed “a PD-1 agonist antibody or antigen-binding fragment thereof”, MPEP 2163 II A 3(a) states: Disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). By the time the invention was made, it is well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three "complementarity determining regions" ("CDRs") which provide the majority of the contact residues for the binding of the antibody to its target epitope. Even a single point mutation in HCDR1 region could lead to antibody lose its binding activity (Ni et al., The Protein Journal, 43, pp. 683-696, July 2024, see Abstract, of record). Thus, the specific antibodies disclosed by the specification would not tell structure of other PD-1 agonist antibodies or variants of thereof . In the instant case, the claims would encompass all possible (known or yet to be discovered) PD-1 agonist antibodies. The specification generally describes a few PD-1 agonist antibodies (see paragraph [0053] of the instant publication). The specification teaches only one PD-1 agonist antibody linked with a MAdCAM-antibody: PMAB18, which has the activities to downregulate several cytokines (see Example 42). The specification and prior art have not established the relationship between the claimed functions and the structure of the agonist antibody. One of ordinary skill in the art would not be able to readily recognize/visualize a PD-1 agonist antibody with the required functions. Taken together, applicant has not provided sufficient evidence to show that the inventors possess a genus of PD-1 agonist antibodies as claimed. Since the specification lacks written description for the broadly claimed PD-1 agonist antibodies or antigen binding fragments, the specification would logically lack written description for the broadly claimed “effector molecule” which is broader than the claimed PD-1 agonist antibodies. Although Applicants may argue that it is possible to screen for PD-1 agonist antibodies that bind and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. "As we held in Lilly, "[a]n adequate written description of a DNA ... 'requires a precise definition, such as by structure, formula, chemical name, or physical properties,' not a mere wish or plan for obtaining the claimed chemical invention." 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171 ). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions." Knowledge of screening methods provides no information about the structure of any future antibodies (other than the PD-1 agonist antibodies disclosed by the instant specification) yet to be discovered that may function as claimed. Claim 24-26 and 31 are drawn methods of treatment using the claimed MAdCAM antibodies. Because the specification lacks written description support for the claimed antibodies, the specification logically lacks written description support for the method of using the claimed antibodies. In addition, as set forth above, the specification does not provide any working examples for “ treating a subject with inflammatory bowel disease, wherein the subject with inflammatory bowel disease has Crohn's disease, or ulcerative colitis” (claims 24 and 25); or “treating a subject with an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, or a GVHD” (claim 26); or “ preventing an autoimmune disorder in a subject at risk for having the autoimmune disorder” (claim 31). These diseases vary significantly, for example, although both Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD), they show unique cytokine profiles, as evidenced by Abstract of Nemeth (Nemeth et al., Cureus, 9(4): e1177, Publication Date: 04/19/2017). CD samples but not UC specimens show significant IL-17, IL-23 and IL-32 expression in comparison to non-IBD (Fig. 2). Specimens from UC (but not from CD) have increased IL-5, IL-13, IL-15 and IL-33 expression compared to non-IBD samples (Fig. 3). Nemeth concludes that an effective treatment may be based on the own physiological needs (Conclusions on page 9). Consistent with this, Allocca (Allocca et al., Expert Opinion on Investigational Drugs, 2018, Vol. 27, NO. 7, 623-629, Publication Date: 07/16/2018) teaches that PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naïve and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn’s disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes (Abstract). Moreover, regarding autoimmune disorders, Autoimmune Diseases (downloaded from: https://my.clevelandclinic.org/health/diseases/21624-autoimmune-diseases, on 12/16/2025) discloses that there are more than 100 autoimmune disorders which can affect almost any tissue or organ in the body (page 3). The causes for many autoimmune diseases are not clear (page 7, para. 1). Autoimmune diseases need a variety of treatments depending on conditions. Everyone’s immune system, genetics and environment are different. That means the treatments may be unique (page 10, para. 1). There might not be any way to prevent autoimmune diseases because experts aren’t sure what cause them (page 11, § Prevention). In view of above, the specification and prior art have not established the relationship between the claimed functions (treating or preventing the claimed diseases) and the structure of the antibodies or antibody-effector conjugates. The ordinary artisan could reasonably conclude based on a survey of the data shown in the instant specification in support of the breadth and scope of the instant claimed antibodies that Applicants were not in possession of the innumerable variants for the antibodies and antibody-effector molecule conjugates. Taken together, the instant specification has not provided a sufficient description for the claimed inventions. 07-31-02 AIA Claim s 24-26 and 31 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 make and/or use the invention. This is an Enablement rejection . To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright , 999 F.2d 1557, 1561 (Fed. Cir.,1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that: The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands , 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman , 230 USPQ 546 (Bd. Apls. 1986) at 547, the court recited eight factors to consider when assessing whether or not a disclosure would require undue experimentation. These factors are: 1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention 5) the state of the art, 6) the relative skill of those in the art, 7) the predictability of the art and 8) the breadth of the claims. These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher , 57 CCPA 1099, 1108,427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons: Nature of invention and breadth of the claims: The claims are drawn to a method of “ treating a subject with inflammatory bowel disease, wherein the subject with inflammatory bowel disease has Crohn's disease, or ulcerative colitis” (claims 24 and 25); or “ treating a subject with an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, or a GVHD” (claim 26); or “ preventing an autoimmune disorder in a subject at risk for having the autoimmune disorder” (claim 31), comprising administering the antibody or antigen binding fragment of claim 7 or a pharmaceutical composition comprising the same. By reciting “wherein the heavy chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO:1445, 1477 or 1480 and the light chain variable region comprises an amino acid sequence having at least 90% identity to the amino acid sequence of SEQ ID NO: 1367” (see claim 7), which would allow up to 10 amino acids changes (such as insertions, deletions, substitutions, or combination thereof). Given Broadest Reasonable Interpretation (BRI), the claims encompass billions of possible variants of SEQ ID NO: 1445 or SEQ ID NO: 1367. As set forth above, the claims also encompass a broad genus of antibody-effector conjugates, as evidenced by claims 17 and 18. Claim 17 recites the antibody or antigen binding fragment is “linked or associated with an effector molecule”. The specification does not limit the term “effector molecule”. Given BRI, “effector molecule” encompasses at least all possible Immune Cell Inhibitory Molecule (ICIM) binding/modulating moieties, Inhibitory Immune Checkpoint (IIC) binding/modulating moieties, Immune Cell Stimulatory Molecule (ICSM) binding/modulating moieties (see paragraphs [0105-0107] of the instant publication US 2024/0010722 A1). Thus, “effector molecule”, which is defined by functions only, would encompass small molecule, peptide, protein, antibody, oligonucleotide, or siRNA, etc… binding to different targets (e.g. targets listed in Table 1 of specification). These compounds vary significantly, have different structures and physical/chemical properties, and function through different mechanisms. In addition, these claims encompass many different diseases, including inflammatory bowel disease (claims 24 and 25), an auto-immune hepatitis, a primary sclerosing cholangitis, a Type 1 diabetes, a transplant, or a GVHD (claim 26), and a broad genus autoimmune disorders (claim 31). Thus, the claims encompass methods of treating or preventing many different diseases by administering a broad genus of antibodies or antibody-effector conjugates. Relative skill in the art : The relative skill of those in the art is high with an MD or a PhD. Level of unpredictability in the art and State of the prior art : These diseases vary significantly, for example, although both Crohn's disease (CD) and ulcerative colitis (UC) are inflammatory bowel diseases (IBD), they show unique cytokine profiles, as evidenced by Abstract of Nemeth (Nemeth et al., Cureus, 9(4): e1177, Publication Date: 04/19/2017). CD samples but not UC specimens show significant IL-17, IL-23 and IL-32 expression in comparison to non-IBD (Fig. 2). Specimens from UC (but not from CD) have increased IL-5, IL-13, IL-15 and IL-33 expression compared to non-IBD samples (Fig. 3). Nemeth concludes that an effective treatment may be based on the own physiological needs (Conclusions on page 9). Based on the teachings, one of ordinary skill in the art would have expected subject with different inflammatory bowel diseases would respond to a certain treatment differently. Consistent with this, Allocca (Allocca et al., Expert Opinion on Investigational Drugs, 2018, Vol. 27, NO. 7, 623-629, Publication Date: 07/16/2018) teaches that PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naïve and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn’s disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes (Abstract). Moreover, the regarding autoimmune disorders, Autoimmune Diseases (downloaded from: https://my.clevelandclinic.org/health/diseases/21624-autoimmune-diseases, on 12/16/2025), there are more than 100 autoimmune disorders which can affect almost any tissue or organ in the body (page 3). The causes for many autoimmune diseases are not clear (page 7, para. 1). Autoimmune diseases can need a variety of treatments depending on conditions. Everyone’s immune system, genetics and environment are different. That means the treatments may be unique (page 10, para. 1). There might not be any way to prevent autoimmune diseases because experts aren’t sure what cause them (page 11, § Prevention). Direction or guidance and working examples: In the instant case, the claims would encompass a large number of MAdCAM antibody variants, unlimited antibody-effector molecule conjugates (which would encompass all possible (known or yet to be discovered) PD-1 agonist antibodies). The specification teaches only one MAdCAM-antibody and effector molecule (PD-1 agonist antibody) conjugate: PMAB18, which has the activities to downregulate several cytokines (see Example 42). The specification does not provide any working examples for any MAdCAM antibody alone or MAdCAM antibody-effector conjugate in treating or preventing any diseases, such as conditions recited by claims 24-26 and 31. The quantity of experimentation needed: The factors outlined in In Re Wands' mentioned above apply here, and in particular as per the MPEP 2164.01 (a): "A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)." It is very clear that one could not make/use this very broad invention that has no working examples in this unpredictable art without undue experimentation. Genetech Inc vs Nova Nordisk 42 USPQ 2d 1001 "A patent is not a hunting license. It is not a reward for search but compensation for its successful conclusion and patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.” Given the numerous antibodies (antibody variants) or antibody-effector conjugates and diseases encompassed by these claims, the lack of specific guidance and the insufficient working examples, undue experimentation would be required of one of skilled in the art to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention . Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b). The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13. The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA/25, or PTO/AIA/26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer. Application No. 18/264,940 Claims 2, 6-8, 11-13, 16-18, 23, 26 and 31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of copending Application No. 18/264,940 (hereinafter Appl. 940). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Appl. 940 teach: 1. A method of treating Type 1 diabetes comprising administering to a subject in need thereof, an anti- PD-1 agonist antibody linked to an anti-MAdCAM antibody , or antigen binding fragment thereof. 2. The method of claim 1, wherein the subject has Type 1 diabetes or is a subject at risk of developing Type 1 diabetes. 4. The method of claim 1, wherein the anti-MAdCAM antibody, or antigen binding fragment thereof, heavy chain variable region comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1499 , a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 1506 , and a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 1507 . 7. The method of any one of claims 1-6, wherein the anti-MAdCAM antibody, or antigen binding fragment thereof, light chain variable region comprises a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 1502 , a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 1497 , and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 1498 . 9. The method of any one of claims 1-8, wherein the anti-MAdCAM antibody, or antigen binding fragment thereof, heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445 , 1477, or 1480 and the anti-MAdCAM antibody light chain variable region comprises an amino acid of SEQ ID NO: 1367 . As shown below, SEQ ID NO: 1445 and SEQ ID NO: 1367 of Appl. 940 are identical to SEQ ID NO: 1445 and SEQ ID NO: 1367 of the instant application, respectively: US-18-264-940-1445 Query Match 100.0%; Score 641; DB 1; Length 119; Best Local Similarity 100.0%; Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLEWVSYISGSGGYTNY 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLEWVSYISGSGGYTNY 60 Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPYYYDMDVWGKGTTVTVSS 119 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPYYYDMDVWGKGTTVTVSS 119 US-18-264-940-1367 Query Match 100.0%; Score 544; DB 1; Length 107; Best Local Similarity 100.0%; Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSSLAWYQQKPGKAPKLLIYAASSLQSGVPS 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSSLAWYQQKPGKAPKLLIYAASSLQSGVPS 60 Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYKSYPVTFGQGTKVEIK 107 ||||||||||||||||||||||||||||||||||||||||||||||| Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYKSYPVTFGQGTKVEIK 107 Thus, although claims of Appl. 940 are drawn to methods, the claims of Appl. 940 disclosed the antii-MAdCAM which would read on antibodies of the instant claims 2, 6, 7, 8, 16. Claim 1 of Appl. 490 also discloses a PD-1 agonist antibody linked to the antibody, which would read on instant claims 17 and 18. Regarding instant claim 11, claim 10 of Appl. 940 teaches wherein the anti-MAdCAM antibody, or antigen binding fragment thereof, heavy chain variable region and the light chain variable region are in a Fab, or an scFv format . Regarding instant claim 12 and 13, the claims of Appl. 940 teach wherein the anti-MAdCAM antibody, or antigen binding fragment thereof, heavy chain variable region and the light variable chain region are linked with a peptide linker (claim 11); wherein the peptide linker is a glycine/serine linker (claim 12). Regarding instant claim 23, the claims of Appl. 940 teach a method of delaying, reducing, treating, or preventing hyperglycemia comprising administering, to a subject in need thereof, a composition comprising an effector molecule linked to an anti-MAdCAM antibody, or antigen binding fragment thereof, and a pharmaceutically acceptable carrier (claim 18); wherein the anti-MAdCAM antibody, or antigen binding fragment thereof, heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445 , 1477, or 1480 and the anti-MAdCAM antibody light chain variable region comprises an amino acid of SEQ ID NO: 1367 (claim 29). Although the claims of Appl. 940 are drawn to a method of treatment, the claims of Appl. 940 disclose the pharmaceutical composition of instant claim 23. Regarding instant claim 26, the claims of Appl. 940 further teach a method of treating Type 1 diabetes comprising administering to a subject in need thereof, an effector molecule linked to an antibody, or antigen binding fragment thereof (claim 13); wherein the effector molecule is a PD-1 agonist (claim 14); wherein the PD-1 agonist is an antibody that binds to PD-1 (claim 15). Regarding instant claim 30, the claims of Appl. 940 further teach a method of delaying, reducing, treating, or preventing hyperglycemia comprising administering, to a subject in need thereof, a composition comprising an effector molecule linked to an anti-MAdCAM antibody, or antigen binding fragment thereof, and a pharmaceutically acceptable carrier (claim 18); wherein the effector molecule is a PD-1 agonist (claim 19); wherein the PD-1 agonist is an antibody that binds to PD-1 (claim 20); wherein the anti-MAdCAM antibody, or antigen binding fragment thereof, heavy chain variable region comprises an amino acid sequence of SEQ ID NOs: 1445 , 1477, or 1480 and the anti-MAdCAM antibody light chain variable region comprises an amino acid of SEQ ID NO: 1367 (claim 29). Because hyperglycemia is a symptom of type 1 diabetes and type 1 diabetes is an autoimmune disease, thus the claims of Appl. 940 above read on the instant claim 30: preventing an autoimmune disorder. This is a provisional nonstatutory double patenting rejection. Claim 14 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of copending Application No. 18/264,940 (hereinafter Appl. 940), as applied to claims 2, 6-8, 11-13, 16-18, 23, 26 and 31 above, and further in view of Huston (Huston et al., PNAS, Vol. 85, pp.5879-5883, Publication Date: August 1988). The claims of Appl. 940 teach claim 12 of the instant application as set forth above. However, the claims of Appl. 940 do not explicitly teach that wherein the peptide linker comprises a sequence of GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 22), GGGGSGGGGSGGGGS (SEQ ID NO: 30), GGGGSGGGGS (SEQ ID NO: 619), GGGGS (SEQ ID NO: 23), or GGGSEGGGSEGGGSE (SEQ ID NO: 1546), or any combination thereof. Huston teaches that connecting VH and VL with a peptide linker to make a scFv with good binding properties (Abstract). Huston teaches the linker is (GGGGS)3 (page 5879, § Gene Synthesis; and Fig. 1). Huston teaches that a single chain biosynthetic antibody binding site was shown to closely mimic the antigen binding affinity and specificity of the parent antibody. Connection of VH and VL by a 15-residue linker may substitute for constant region contacts in the Fab and thereby aid recovery of native binding properties (the bridging paragraph of pages 5882-5883). It would have prima facie been obvious to one of ordinarily skilled in the art at the time the invention was filed to use a glycine/serine linker to connect heavy chain variable region and light chain variable region as taught by the claims of Appl. 940, and to use the 15 -residue linker (GGGGS)3 as taught by Huston with reasonable expectation of success, because the linker has been tested in scFv format and can generate scFv with similar antigen binding affinity and specificity compared to the parent antibody. The motivation would have been to use a well-tested linker for making a good scFv specific for MAdCAM. Application No. 18/547,183 08-35 AIA Claim s 2, 6-8, 11-14, 16-18, 23, 24, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim s 1, 2, 7, 12-14, 16-19, 21, 23, 24, 26, 28, 31, 33-36, 38-42 of copending Application No. 18/547,183 (hereinafter Appl. 183) . Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Appl. 183 teach: 1. (Currently Amended) An antibody, or antigen binding fragment thereof, comprising a heavy chain variable region and a light chain variable region, wherein: the heavy chain variable region comprises … the amino acid sequence of SEQ ID NO: 1718 or 1729. 21. (Currently Amended) The antibody, or antigen binding fragment thereof of claims 1, wherein the antibody is linked or associated with another antibody or targeting moiety, optionally wherein the another antibody or targeting moiety binds to MAdCAM. 28. (Currently Amended) The antibody, or antigen binding fragment thereof of claim 26, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 1445 and/or the light chain variable region comprises the amino acid sequence of SEQ ID NO: 1367. As shown below, SEQ ID NO: 1445 and SEQ ID NO: 1367 of Appl. 183 are identical to SEQ ID NO: 1445 and SEQ ID NO: 1367 of the instant application, respectively: US-18-547-183-1445 Query Match 100.0%; Score 641; DB 1; Length 119; Best Local Similarity 100.0%; Matches 119; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLEWVSYISGSGGYTNY 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLEWVSYISGSGGYTNY 60 Qy 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPYYYDMDVWGKGTTVTVSS 119 ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDRPYYYDMDVWGKGTTVTVSS 119 US-18-547-183-1367 Query Match 100.0%; Score 544; DB 1; Length 107; Best Local Similarity 100.0%; Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0; Qy 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSSLAWYQQKPGKAPKLLIYAASSLQSGVPS 60 |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||| Db 1 DIQMTQSPSSLSASVGDRVTITCRASQSISSSLAWYQQKPGKAPKLLIYAASSLQSGVPS 60 Qy 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYKSYPVTFGQGTKVEIK 107 ||||||||||||||||||||||||||||||||||||||||||||||| Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCQQYKSYPVTFGQGTKVEIK 107 33. (Original) A PD-1 agonist comprising four polypeptide chains, wherein the four polypeptide chains comprise: Chain 1: N terminus (nt)-VH1-CH1-CH2-CH3- Linker A- scFv [VL2- Linker B -VH2]-C terminus (ct); Chain 2: nt-VH1-CH1-CH2-CH3-Linker A- scFv [VL2-Linker B-VH2]-ct; Chain 3: nt-VLI-CK-ct; and Chain 4: nt-VLI-CK-ct;wherein: VH1 comprises the sequence of SEQ ID NO: 1476; CH1-CH2-CH3 comprises the sequence of SEQ ID NO: 44; Linker A comprises the sequence of SEQ ID NO: 30; VL2 comprises the sequence of SEQ ID NO: 1445 ; Linker B comprises the sequence of SEQ ID NO: 22 ; VH2 comprises the sequence of SEQ ID NO: 1367 ; VL1 comprises the sequence of SEQ ID NO: 1359; and CK comprises the sequence of SEQ ID NO: 45, linked by a linker of SEQ ID NO: 22. As evidenced by Sequence Listing of 08/21/2023, SEQ ID NO: 22 has the sequence: GGGGSGGGGSGGGGSGGGGS. Thus, claim 33 of Appl. 183 teach an anti-MAdCAM antibody comprising VL of SEQ ID NO: 1445 and VH of SEQ ID NO: 1367 in scFv format, wherein the anti-MAdCAM antibody is linked with a PD-1 agonist antibody. The composition of claim 33 of Appl. 183 reads on instant claims 1, 6-8, 11-14, 16-18. Regarding instant claim 23, the claims of Appl. 183 teach a pharmaceutical composition comprising the antibody, or antigen binding fragment thereof of claim 1 and a pharmaceutically acceptable carrier (claim 35). Regarding instant claim 24, the claims of Appl. 183 teach a method of treating inflammatory bowel disease, the method comprising administering an antibody, or antigen binding fragment thereof of claim 1 to a subject in need thereof (claim 36). Regarding instant claim 26, the claims of Appl. 183 teach a method of treating auto-immune hepatitis, primary sclerosing cholangitis, Type 1 diabetes, graft-versus-host disease (GVHD), or an autoimmune disorder, the method comprising administering an antibody, or antigen binding fragment thereof of claim 1 to a subject in need thereof . This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented. Related Prior Art Duijvestein (Duijvestein et al., Expert Opinion on Biological Therapy, 2019, Vol. 19, No. 4, 361-366, Publication Date: 02/11/2019) teaches: “Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expression in gut-associated lymphoid tissue is upregulated in patients with inflammatory bowel disease (IBD). Blocking adhesion molecules and thereby inhibiting migration of lymphocytes into sites of inflammation in the gut is an attractive new treatment target in drug development for IBD. This review discusses the preclinical and clinical experience on SHP647 (previously called PF-00547659 and PF-00547,659), a fully human IgG2K monoclonal antibody that binds to MAdCAM-1 to selectively reduce lymphocyte homing to the intestinal tract. Blocking endothelial adhesion molecule MAdCAM−1 could represent an attractive target for the treatment of IBD. In the next years, the results from the phase III studies as well as data to support therapeutic drug monitoring based on drug levels to guide and optimize individual therapy will become available. Furthermore, much effort is put in the development of clinical prediction models to predict which drug is optimal for an individual patient”. See Abstract. Duijvestein teaches MAdCAM-1 antibody and a method of treating IBD using the antibody. However, Duijvestein does not teach the specific CDR combination for MAdCAM antibody, or antibody linked with an effector molecule such as a PD-1 agonist antibody. Thompson (Thompson et al., US 2020/0199247 A1, Publication Date: 06/25/2020, cited in IDS of 08/21/2023) teaches antibody conjugates of immune-modulatory compounds and pharmaceutical compositions for use in the treatment of disease, such as autoimmune disease (Abstract). Thompson teaches that the antibody can be an antibody to MAdCAM ([0005]). However, Thompson does not teach the specific CDR combination for MAdCAM antibody, or antibody linked with an effector molecule such as a PD-1 agonist antibody. Conclusion No claims are allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHENG LU whose telephone number is (571)272-0334. The examiner can normally be reached Monday-Friday 8-5. 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) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /CHENG LU/ Examiner, Art Unit 1642 Application/Control Number: 18/252,081 Page 2 Art Unit: 1642 Application/Control Number: 18/252,081 Page 3 Art Unit: 1642 Application/Control Number: 18/252,081 Page 4 Art Unit: 1642 Application/Control Number: 18/252,081 Page 5 Art Unit: 1642 Application/Control Number: 18/252,081 Page 6 Art Unit: 1642 Application/Control Number: 18/252,081 Page 7 Art Unit: 1642 Application/Control Number: 18/252,081 Page 8 Art Unit: 1642 Application/Control Number: 18/252,081 Page 9 Art Unit: 1642 Application/Control Number: 18/252,081 Page 10 Art Unit: 1642 Application/Control Number: 18/252,081 Page 11 Art Unit: 1642 Application/Control Number: 18/252,081 Page 12 Art Unit: 1642 Application/Control Number: 18/252,081 Page 13 Art Unit: 1642 Application/Control Number: 18/252,081 Page 14 Art Unit: 1642 Application/Control Number: 18/252,081 Page 15 Art Unit: 1642 Application/Control Number: 18/252,081 Page 16 Art Unit: 1642 Application/Control Number: 18/252,081 Page 17 Art Unit: 1642 Application/Control Number: 18/252,081 Page 18 Art Unit: 1642 Application/Control Number: 18/252,081 Page 19 Art Unit: 1642 Application/Control Number: 18/252,081 Page 20 Art Unit: 1642 Application/Control Number: 18/252,081 Page 21 Art Unit: 1642 Application/Control Number: 18/252,081 Page 22 Art Unit: 1642 Application/Control Number: 18/252,081 Page 23 Art Unit: 1642 Application/Control Number: 18/252,081 Page 24 Art Unit: 1642 Application/Control Number: 18/252,081 Page 25 Art Unit: 1642