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 .
Election/Restrictions
2. Applicant’s election of eGFP as the species of tracking component (fluorescent dye), anti-HER2 as the species of targeting component (tumor associated antigen), FHR4 as the species of effector component (factor capable of modulating the complement system), and trifunctional multi-FH4/multi-VHH anti-Her2/mono-eGFP as the species of a fully-defined molecular embodiment in the reply filed on 10 December 2025 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)).
3. Claims 41 and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10 December 2025.
4. The requirement is still deemed proper and is therefore made FINAL.
Information Disclosure Statement
5. The information disclosure statements (IDS) submitted on 02 November 2022, 01 September 2023 and 18 July 2024 have been considered by the examiner.
Status of Application, Amendments, and/or Claims
6. The response filed on 10 December 2025 has been entered in full. Claims 41 and 47 have been withdrawn as indicated supra. Therefore claims 36-47 are pending, and claims 36-40 and 42-46 are the subject of this Office Action.
Claim Objections
7. Claim 36 is objected to because of the following informalities: The claim recites “C4bp” without first providing the full name of the term. It is suggested that the term be spelled out at its first use and in all independent claims. Appropriate correction is required.
8. Claim 36 is objected to because of the following informalities: The limitation “the C4bp” (lines 11 and 12) should recite “a C4bp”. Appropriate correction is required.
Improper Markush
9. Claims 36-40 and 42-46 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of functional components (i.e., synthetic or natural peptides, polypeptides, proteins, peptide analogues, peptidomimetics, antibodies, antibody fragments and derivatives thereof) (claim 36), targeting components (i.e., antibodies, binding fragments thereof, ligands to a target cell receptor and soluble receptors) (claim 42) and targeting components (i.e., antibody or fragment thereof directed against tumor-associated antigen HER2/neu or scFv anti-GYPA) (claim 46) is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Claims 36, 42, and 46 (and claims dependent thereon) are directed to different molecules having different structures, and thus share no structural similarity. Therefore, there is no substantial structural feature and a common use that flows from the substantial structural feature.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
10. 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.
11. Claims 36-40 and 42-46 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.
12. The claims are drawn quite broadly to a multifunctional heteromultimeric protein complex, comprising three or more different functional components present in a defined relative ratio; wherein the three or more different functional components are each independently selected from a tracking component, a targeting component and an effector component and wherein said functional components comprise said tracking component, one or more of said targeting components and one or more of said effector components; wherein said functional components are selected from the group comprising synthetic or natural peptides, polypeptides, proteins, peptide analogues, peptidomimetics, antibodies, antibody fragments and derivatives thereof; wherein said multifunctional heteromultimeric protein complex comprises eight multimerizing scaffold polypeptides, of which seven are a C-terminal part of the alpha-chain of the C4bp multimer and one is a C-terminal part of the beta-chain of the C4bp multimer; and wherein said tracking component is fused to said C-terminal part of the beta-chain of the C4bp multimer and said one or more targeting components and said one or more effector components are each fused to one or more of said C-terminal part of said alpha chain of the C4bp multimer. The claims also recite wherein said one or more targeting components allow binding of the multifunctional heteromultimeric protein complex to a target cell and are selected from antibodies, binding fragments thereof, ligands to a target cell receptor and soluble receptors, or wherein at least one of the targeting components is an antibody directed against a tumor antigen, against a surface marker of erythrocytes or against a pathogen-associated surface marker. The claims also recite wherein said one or more effector components are factors capable of modulating the complement system and/or factors capable of activating antibody-dependent cell mediated cytotoxicity (ADCC), or is a factor capable of modulating the complement system selected from factor H-related protein 4 (FHR4) and Properdin. Thus the claims are drawn to a large genus of multifunctional heteromultimeric protein complexes that comprise at least three or more functional components (a targeting component, an effector component, or a tracking component), and a scaffold polypeptide having no particular structural feature. However, the specification does not provide sufficient written description as to the structural features of the claimed genus of multifunctional heteromultimeric protein complexes that are encompassed by the claims, nor does it describe a representative number of species that have the recited function of being useful for treating a solid tumor in a mammalian subject.
13. To provide adequate written description and evidence of possession of a recited genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In this case, the only factor present in the claims is a multifunctional heteromultimeric protein complex that comprises least two different functional components, (targeting component; an effector component; or tracking component), and a multimerizing scaffold polypeptide. The claims recite the effector component as being a factor capable of modulating the complement system. Thus, the claims encompass a large genus of heteromultimeric protein complex comprising targeting and functional components, with no requirement for any particular structural feature or function for the recited tracking, targeting or effector components.
14. In contrast to the breadth of the claims, the specification discloses a multifunctional heteromultimeric protein that comprises (a) C4b-binding protein (C4bp) (b) multivalent FHR4; (c) multivalent VHH against HER2; and (d) a monovalent enhanced GFP (eGFP) tracking function (TrF), (see page 50, lines 25-35 and figure 2). The specification teaches that CAP-effector function (EF) and targeting function (TaF) are cloned in the cassette for EF or TaF functions and that VHH anti-Her2 upstream of C4bpa and the hinge, CH2 and CH3 domains of IgG ('Fc') downstream of C4bpa and a nucleic acid vector encoding a tracking function (e.g. encoding eGFP upstream of C4bp, (see page 60). However, the claims encompass multifunctional heteromultimeric protein complexes that comprise, at least two different functional components, targeting components, effector component or tracking component, with no requirement for any particular structural feature or function for the recited tracking, targeting or effector components.
15. A "representative number of species" means that the species, which are adequately 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. The disclosure of only one 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."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)(Claims directed to PTFE dental floss with a friction-enhancing coating were not supported by a disclosure of a microcrystalline wax coating where there was no evidence in the disclosure or anywhere else in the record showing applicant conveyed that any other coating was suitable for a PTFE dental floss.).
16. The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AlA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
17. With regard to the targeting (i.e., antibody) components recited in the claims. while generically the structure of antibodies is known, the structure of the presently recited antibodies to be produced and screened in the instant method can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” (See p. 8, lines 3-5 of WO 2009/033743 A1). Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of claimed antibodies.
18. 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).
19. 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).
20. For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species, cannot be achieved by disclosing only one or two species within the genus. See, e.g., Eli Lilly. Description of a representative number of species does not require the description to be of such specificity that it would provide individual support for each species that the genus embraces. If a representative number of adequately described species are not disclosed for a genus, the claim to that genus must be rejected as lacking adequate written description under 35 U.S.C. 112, first paragraph.
21. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, 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 antibodies, 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.
22. One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence.
23. Therefore, Applicant has not disclosed sufficient species or common structural features such that one skilled in the art would conclude that Applicant was in possession of the claimed genus of heteromultimeric protein complexes. Accordingly, claims 36-40 and 42-46 do not meet the written description provision of 35 U.S.C. §112a) or 35 U.S.C. 112 (pre-AIA ) first paragraph. 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).
Double Patenting
24. 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 claims at issue 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); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
25. 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
26. The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
27. Claims 36-40 and 42-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,518,791.
28. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘791 patent recite multifunctional heteromultimeric protein complexes comprising three or more functional components in a defined ratio, wherein the three or more different functional components are species of tracking components, targeting components, and effector components that are encompassed by the genus of said components recited in the instant claims. Thus the claims are overlapping in scope.
Summary
29. No claim is allowed.
Advisory Information
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/JON M LOCKARD/Examiner, Art Unit 1647 March 7, 2026