Notice of Pre-AIA or AIA Status
1. 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
Election/Restrictions
2. Applicant's election without traverse of Group I, claims 1-9, 14-17 and 20, in the reply filed on 22 December 2025 is acknowledged. Claims 10-13 and 18-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 22 December 2025.
3. The restriction requirement is still deemed proper and is therefore made FINAL.
Status of Application, Amendments, and/or Claims
4. The Response to the Restriction Requirement filed 12 December 2025 has been entered in full. Claims 10-13 and 18-19 have been withdrawn as discussed supra. Therefore, 1-20 are pending, and claims 1-9, 14-17 and 20 are the subject of this Office Action.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 09 January 2023 and 21 November 2023 have been considered by the Examiner.
Claim Rejections - 35 USC § 112, 1st Paragraph (Written Description)
6. The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
7. Claims 1-9, 14-17 and 20 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.
8. The U.S. Court of Appeals for the Federal Circuit recently reaffirmed, in an en banc decision, that the written description requirement for a genus may be satisfied either by (i) the disclosure of a representative number of species falling within the scope of the genus or (ii) structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Ariad Pharmaceuticals', Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350, 94 U.S.P.Q.2d 1161, 1171 (en banc) (Fed. Cir. 2010), citing Regents" of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69, 43 U.S.P.Q.2d 1398, 1406 (Fed. Cir. 1997).
9. The representative ways of satisfying the written description requirement as set out by the Federal Circuit in Ariad Pharmaceuticals comport with statements set out in the USPTO's Manual of Patent Examining Procedure (M.P.E.P.). In particular, the M.P.E.P. provides that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species of relevant identifying characteristics. M.P.E.P. § 2163, II, A, 3, (a), (ii).
10. 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: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP § 2163.
11. The claims are drawn very broadly to a polypeptide comprising an amino acid sequence of MAdCAM-1 capable of binding α4β7 integrin, wherein said polypeptide is in association with a therapeutic moiety, wherein said therapeutic moiety is not a constant region of an antibody. The claims also recite wherein the first target is a T-cell antigen polypeptide, and the second target is a cancer cell surface polypeptide. The claims also recite wherein said amino acid sequence of MAdCAM-1 does not comprise a functional Mucin-like domain, wherein said amino acid sequence of MAdCAM-1 is more than 5 amino acids in length or wherein said amino acid sequence of MAdCAM-1 comprises SEQ ID NO: 21. The claims also recite wherein said amino acid sequence of MAdCAM-1 comprises: (i) an amino acid sequence of a first Ig-like domain (D1) located N to C in a full length MAdCAM-1; (ii) an amino acid sequence of a second Ig-like domain (D2) located N to C in a full length MAdCAM-1; or (iii) an amino acid sequence of a first Ig-like domain (D1) and a second Ig-like domain (D2) located N to C in a full length MAdCAM-1. The claims also recite targeted particle comprising a therapeutic and/or a detectable moiety, said particle is attached to a polypeptide comprising an amino acid sequence of MAdCAM-1. Thus, the claims have been broadly interpreted by the Examiner as reading upon an extremely large genus of polypeptides that are only defined by a very limited structure and a desired function/activity.
12. For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
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.”), see MPEP 2163.IIAii.
13. Several recent court decisions speak to the notion that claiming a molecule with unknowable structural heterogeneity solely by reciting its function is not sufficient to establish possession of a genus so claimed.
14. For example, quoting Eli Lilly the court states in Ariad, 598 F.3d at 1350: "[A] sufficient description of a genus requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." (quoting Eli Lilly, 119 F.3d at 1568-69).
15. A "representative number of species" means that the species which are described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG V. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
16. In the instant case, the claims encompass in their breadth “an amino acid sequence of MAdCAM-1, which the specification defines as "an amino acid sequence of MAdCAM-1" refers to full length MAdCAM-1 or a fragment thereof or a homolog thereof which maintains at least the α4β7 integrin binding capability of the full length MAdCAM-1. The homolog (naturally occurring or synthetically/recombinantly produced) can be, for example, at least 70 %, at least 75%, at least 80 %, at least 81 %, at least 82 %, at least 83 %, at least 84 %, at least 85 %, at least 86 %, at least 87 %, at least 88 %, at least 89 %, at least 90 %, at least 91 %, at least 92 %, at least 93 %, at least 94 %, at least 95 %, at least 96 %, at least 97 %, at least 98 %, at least 99 % or100 % identical or homologous to the polypeptide provided in SEQ ID NO: 23-27 or a functional fragment thereof which exhibit the desired activity (i.e., at least binding a α4β7 integrin” (See pg. 13, lines 20-30); or wherein the amino acid sequence is more than 5 amino acids in length, or comprises an amino acid sequence of a first Ig-like domain (D1) and an amino acid sequence of a second Ig-like domain (D2). It is noted that the recitation of “an amino acid sequence of a first Ig-like domain (D1)”, for example, can be interpreted to mean a partial sequence comprising as few as 2 amino acids of a first Ig-like domain (D1).
17. Given the exceedingly large genus of polypeptides defined by only 4 amino acid residues (i.e., SEQ ID NO: 21), or having as little as 70 % sequence identity to a defined sequence, or a functional fragment thereof, one of skill in the art cannot possibly envision structures contained within this genus that will be capable of binding α4β7 integrin. While the specification provides adequate written description for a MAdCAM-1 Fc fusion protein which comprises: a domain D1 comprising the amino acid sequence of SEQ ID NO: 11), domain D2 comprising the amino acid sequence of SEQ ID NO: 12 and Fc domain comprising the amino acid sequence of SEQ ID NO: 13, which is disclosed as binding to high affinity α4β7 integrin expressed on TK-1 cells this single embodiment of the invention is not representative of the unlimited breadth of the claimed invention which includes the fragments and variants recited in the claims. The Specification also provides adequate written description of said MAdCAM-1 Fc fusion protein conjugated to 64Cu-labled NOTA (See pg. 57); lipid nanoparticles (LNPs) comprising said MAdCAM-1 Fc fusion protein which bound high affinity α4β7 integrin (See Example 2 at pp. 58-59), and LNPs encapsulating CD45 siRNA with the MAdCAM-1 Fc fusion protein attached thereto (See Example 3 at pg. 60)
18. The state of the art is such that the relationship between the sequence of a protein and its activity is not well understood and unpredictable, and that certain positions in the sequence are critical to the protein’s structure/function relationship and can only tolerate only relatively conservative substitutions or no substitutions. The problem of predicting protein and DNA structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein and DNA is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein, the positions within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of success are limited. Certain positions in the sequence are critical to the protein's structure/function relationship, e.g. such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These regions can tolerate only relatively conservative substitutions or no substitutions (see Wells, 1990, Biochemistry 29:8509-8517; Ngo et al., 1994, The Protein Folding Problem and Tertiary Structure Prediction, pp. 492-495). While Specification outlines art-recognized procedures for producing variants, this is not adequate guidance as to the nature of the active variants that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation. An ordinary artisan would immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active, which conformation is dependent upon surrounding residues; therefore substitution of non-essential residues can often destroy activity. The art recognizes that function cannot be predicted from structure alone (Skolnick et al., 2000, Trends in Biotech. 18(1):34-39, especially p. 36 at Box 2; cited by Applicant).
19. Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
20. An adequate written description of a chemical invention requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”). See MPEP 2163IIA3(a).
11. Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of MAdCAM-1 polypeptides capable of binding α4β7 encompassed in the breadth of the instant claims.
22. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states that in order to satisfy the written description requirement, “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). As discussed above, the skilled artisan cannot envision the detailed structure of the encompassed genus of bispecific polypeptide complexes comprising an MM1 and MM2 capable of masking the binding of any first and second targeting domain, respectively, to any T-cell antigen and any tumor cell antigen, 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.
23. Without a correlation between structure and function, the claims do little more than define the claimed invention by function, which is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 ("definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is").
Claim Rejections - 35 USC § 103
24. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
25. 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.
26. The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
27. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
28. Claims 1-9, 14-17 and 20 is/are rejected under 35 U.S.C. 103 as being obvious over Peer et al. (WO 2009/026328; published 26 February 2009; cited by Applicant) in view of Briskin et al. (Us 2013/0022607; published 24 January 2013; cited by Applicant),
29. Peer et al. discloses a leukocyte-selective delivery agent comprising, (a) a targeting moiety that selectively binds one or more integrins on the surface of a leukocyte; (b) a carrier particle associated with the targeting moiety, wherein the carrier particle having a lipid phase and an aqueous phase; (c) an insoluble agent entrapped in the lipid phase of the carrier particle; and/or (d) a soluble agent entrapped in the aqueous phase of the carrier particle (See claim 12).
Peer et al. also discloses wherein the integrin can be α4β7 and wherein the integrin can bind an integrin ligand such as MAdCAM-1 (See claims 14-15), and wherein the targeting moiety comprises an antibody or integrin ligand, or functional fragments or variants thereof (See claim 17). Peer et al. also discloses that association between a targeting moiety with a carrier particle for example liposome, wherein the targeting moiety and the carrier particle are attached via a linker moiety (See pg. 57[0024]).
Peer et al. teaches that the agent refers to any chemical entity or biological product administered to a subject to treat or prevent or control a disease or condition, referred to as "therapeutic agents". An agent for use in can affect the body therapeutically, such as siRNA (See pg. 24 [086])).
30. Peer et al. does not specifically teach wherein the delivery agent comprises MAdCAM-1 as claimed in the present application.
31. Briskin et al. discloses a human MAdCAM-1 moiety fused at its Cterminus to the N-terminus of an immunoglobulin moiety, and further discloses a portion of MAdCAM-1 which is sufficient for binding to a ligand (e.g., α4β7 integrin), such as the complete extracellular domain or a portion thereof comprising the two N-terminal immunoglobulin domains, D1 (which comprises the amino acid sequence of SEQ ID NO: 21 of the instant application; See pg. 6[0056]) and D2, in which the transmembrane region and functional Mucin-like domain is deleted, is used (See pp. 4-5 [0046]). It is noted that the disclosed D1 and D2 domains of human MAdCAM-1 would comprise the amino acid sequence of SEQ ID NO: 22 of the instant application, as evidenced by Ni et al. (WO 98/20110; published 14 May 1998, See SEQ ID NO: 46).
32. It would have been obvious for a person skilled in the art to use the α4β7 ligand MAdCAM-1 as a targeting ligand for a therapeutic moiety and/or a detectable moiety, and to use a fragment of MAdCAM-1 that comprises the two lg-like domains (Dl and D2) and does not comprise the transmembrane domain or a functional Mucin-like domain.
33. The motivation to do so is provided by Peer et al. who disclose that selective targeting of the activated and adhesive leukocytes would be useful for suppressing inflammatory tissue injury caused by leukocyte accumulation (paragraph 065), and it was known that the expression of MAdCAM-1 is limited to the gut, and upregulated in the gut by colitis (paragraph 009) therefore it was obvious for a person skilled in art to use the leukocyte selective delivery agent as disclosed in Peer et al. for the treatment of disease associated with inflammation, and to use a fragment of MAdCAM-1 that comprises the two lg-like domains (Dl and D2) and does not comprise the transmembrane domain or a functional Mucin-like domain which is sufficient for binding to α4β7, as taught by Briskin et al. The expectation of success is high since methods of making fusion proteins is well-known and routine in the art.
34. Accordingly, the invention, taken as a whole, is prima facie obvious over the combined teachings of the prior art.
Summary
35. No claim is allowed.
Advisory Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jon M. Lockard whose telephone number is (571) 272-2717. The examiner can normally be reached on Monday through Friday, 8:00 AM to 4:30 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Joanne Hama, can be reached on (571) 272-2911. The fax number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JON M LOCKARD/
Examiner, Art Unit 1647
April 3, 2026
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