DETAILED OFFICE ACTION
The present application is being examined under the pre-AIA first to invent provisions.
The request filed on 17 July 2025 for a Continued Examination (RCE) under 37 CFR 1.114 based on parent Application No. 17/679,675 is acceptable, and an RCE has been established. An action on the RCE follows.
Applicant’s amendment filed on 17 July 2025 is acknowledged and entered. Following the amendment, claims 7, 8, 14, 16, 18, and 19 are canceled, and claims 1, 15, 17 and 20 are amended.
Currently, claims 1, 10, 12, 13, 15, 17 and 20 are pending, and claims 1, 10, 15, 17 and 20 are under consideration. Claims 12 and 13 remain withdrawn from further consideration as being drawn to a non-elected invention.
Withdrawal of Objections and Rejections:
All objections and rejections of claims 7, 8, 14, 16, 18 and 19 are moot as the applicant has canceled the claims.
The rejection of claim 20 under 35 U.S.C. 112(b), as being indefinite is withdrawn in view of applicant’s amendment.
Formal Matters:
Information Disclosure Statement
Applicant's IDS submitted on 9/10/2025 is acknowledged and has been considered. A signed copy is attached hereto.
Claims
Claims 1 and 15 are objected to for encompassing a non-elected subject matter: CDR1 and CDR2 of SEQ ID NO: 238 and 380, respectively; i.e., the elected VHH of SEQ ID NO: 623 does not comprise CDR1 and CDR2 of SEQ ID NO: 238 and 380, respectively. The applicant is required to amend the claims to read only upon the elected invention.
Rejections under 35 U.S.C. §112:
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.
Written Description
Claims 1, 10, 15 and 17 remain 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, for the reasons of record set forth in the previous Office Actions mailed on 11/7/2024, and 4/17/2025.
Applicants argument filed on 17 July 2025 has been fully considered, but is not deemed persuasive for the reasons below.
At pages 7-9 of the response, the applicant made similar arguments as previously: the specification provides both disclosure of numerous species falling within the scope of the claims and description of structural features common to members of the genus, as the specification discloses at least 71 VHH sequences containing various CDRs (Table A1 and Figure 5), and all of which are characterized as capable of binding to IL-17A and/or IL-17F, and 71 embodiments is more than adequate disclosure of a representative number of species of the genus of polypeptides which has been claimed; the specification also provides guidance and description with regard to structural features common to members of the genus so that one of skill in the art can immediately "visualize or recognize" the members of the genus, for example, camelid-derived, VHH-based domain- containing polypeptides may have the following general structure: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4; and specific CDR sequences from the 71 VHH clones (Table B-1), although the invention is not so limited; that the specification provides guidance with regard to parts and/or fragments of the polypeptides disclosed therein which may be combined (including fragments having as little as 50% sequence identity; each CDR can be replaced by a CDR chosen from the group consisting of amino acid sequences that have at least 80% ... sequence identity with the mentioned CDR's
(p. 168, and p. 129); and the specification further discloses hallmark residues present through such sequences, for example, the specification teaches that preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47 83, 84, 103, 104, and 108 according to the Kabat numbering are chosen from the hallmark residues mentioned in Table B-2 (see p. 67, and p. 158); thus, the specification describes a representative number of species of the claimed genus as well as guidance and description with regard to structural features common to members of the genus so that one of skill in the art can immediately "visualize or recognize" the members of the genus.
This argument is not persuasive for the reasons of record. Once again, while the specification discloses 71 VHH clones (SEQ ID NOs: 623-693), it does not teach any (0) % variant based on any of SEQ ID NOs: 623-693, especially substitutions in the CDR regions based on a particular CDR or CDRs, as claimed. The claims are extremely broad, more importantly, they encompass variants comprising amino acid substitutions in all 3 CDRs: wherein each of the 3 CDRs is selected from two sequences with no sequence similarity, and variants thereof: CDR1 can be either SEQ ID NO: 238 or 197, or their variant having 1 amino acid difference (given that SEQ ID NO: 238 only has 3 amino acids); CDR2 can be either SEQ ID NO: 380 or 339, or their variant having 1-7 amino acid differences; and CDR3 can be either SEQ ID NO: 481 or its variant having 1-3 amino acid differences. As such, the claims encompass an infinite number of VHH variants due to countless possible combinations of amino acid substitutions, and “mix and match” of the encompassed CDRs (including the variants), while only 71 VHH clones are disclosed, and 0 species (CDR variant) is made based on any of SEQ ID NOs: 623-693, or any of the CDRs, which meets the limitations of the claims. Thus, one of skill in the art cannot "visualize or recognize" the members of the claimed genus of the variant. Furthermore, as discussed previously, while the specification discloses the 71 VHH clones, it does not teach the structural and functional relationship for the antibodies, specifically, in the CDR regions, and there is no regularity that can be followed from the sequences of the CDR regions of the 71 VHH clones to make a particular variant of a CDR; and there is no guidance in the specification as to which CDRs can be “mixed and matched” while retaining the desired functional activity of the VHH. For example, the recited CDR3 of SEQ ID NO: 481 is not appeared or used in any of the other 70 VHH clones, and there is no evidence that the CDR3 of SEQ ID NO: 481 can be “mixed or matched” with any other CDR1 and CDR2 of the other 70 VHH clones to form a functional VHH, let alone a variant of the CDR3 of SEQ ID NO: 481 comprising 1-3 amino acid substitutions. Similarly, the CDR1 of SEQ ID NO: 238 appears in 5 of the 71 VHH clones, three of which share the 3 identical CDRs, and the CDR2 and/or CDR3 of the other two clones comprise 1 amino acid substitution as compared to that in the 3 clones; and SEQ ID NO: 238 shares no sequence similarity to any CDR1 of the other 66 VHH clones. Therefore, again, there is no evidence that the CDR1 of SEQ ID NO: 238 can be “mixed or matched” with any other CDR2 and CDR3 of the 66 VHH clones to form a functional VHH, let alone a variant of the CDR1 of SEQ ID NO: 238 comprising 1 amino acid substitution. In addition, the CDR1 of SEQ ID NO: 238 comprises only 3 residues; and one amino acid substitution would count for 1/3 of sequence variation. There is no evidence of any kind that such change would result in a functional VHH, let alone, being “mixed and matched” with any other encompassed CDR and CDR3 and variants thereof. Therefore, even though the specification discloses 71 VHH clones, their sequences reveal that it is unpredictable as to the effect of the sequence changes in a particular VHH in functional property, especially in the CDR regions given that CDRs are responsible for the functional activity and antigen specificity of an antibody, and are highly sensitive to any change in sequence structure.
Furthermore, once again, with respect to applicant argument that the specification provides guidance and description with regard to structural features common to members of the genus (FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4) so that one of skill in the art can immediately "visualize or recognize" the members of the genus, and provides guidance with regard to parts and/or fragments of the polypeptides disclosed therein which may be combined, it is unclear as to how the general structure FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4, in any way, would make one skilled in the art to visualize or recognize the encompassed specific VHH antibodies of the genus as claimed? Additionally, with respect to applicants argument that the specification teaches that preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104, and 108 according to the Kabat numbering are chosen from the hallmark residues mentioned in Table B-2, these amino acid residues at said positions represent the residues in the framework regions (FRs). Therefore, such does not in any way support the CDR variants as claimed. Furthermore, with respect to the argument that the specification provides guidance with regard to parts and/or fragments of the polypeptides disclosed therein which may be combined (including fragments having as little as 50% sequence identity; each CDR can be replaced by a CDR chosen from the group consisting of amino acid sequences that have at least 80% ... sequence identity with the mentioned CDR's, once again, the issue is not whether one skilled in the art would know how to follow the general structure of a VHH, to calculate % sequence identity, to make an antibody variant, and to test/characterize the antibody; rather, the issue is that the present application does not provide adequate written description for the claimed genus of the polypeptides. "Possession may not be shown by merely describing how to obtain possession of members of the claimed genus." Ex parte Kubin, 83 USPQ2d 1410, 1417 (BPAI 2007) (citing Rochester, 358 F.3d at 927). The first paragraph of 35 U.S.C. § 112 "requires a 'written description of the invention' which is separate and distinct from the enablement requirement." Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563 (Fed. Cir. 1991). An adequate written description of a chemical invention "requires a precise definition, such as by structure, formula, chemical name, or physical properties." University of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 927 (Fed. Cir. 2004); Regents of the Univ. of Cal. v. Eli Lilly & Co., Inc., 119 F.3d 1559, 1566 (Fed. Cir. 1997); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993). "A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F.3d at 923; Eli Lilly, 119 at 1568. Instead, the "disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described." Id.
At pages 9-10 of the response, the applicant argues that the case law permits genus claims with even a very large degree of variation as long as the recited genus is supported by (1) disclosure of a representative number of species falling within the scope of the genus, or (2) description of structural features common to the members of the genus so that one of skill in the art can immediately "visualize or recognize" the members of the genus, which Applicant has as established above; that, with regard to the variation present within a CDR, even a brief check of the sequences disclosed in Table B-1 shows that Applicant specifically discloses examples of nanobodies having a second CDR which differs from SEQ ID NO: 380 or SEQ ID NO: 339 by even more than 1-7 amino acids, thus, claims 1, 10, 15, and 17 are adequately supported by the specification as originally filed.
This argument is not persuasive for the reasons of record and above.
Once again, only the VHH comprising all three CDRs of SEQ ID NO: 197, 339 and 481, or comprising the amino acid sequence of SEQ ID NO: 623; but not the full breadth of the claims (various CDR variants as claimed, and VHH having “mixed and matched” CDRs) meets the written description provision of 35 U.S.C. §112, 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).
Rejections Over Prior Art:
Claim interpretation: claim 20 is interpreted as being directed to a polypeptide comprising a camelid-derived, VHH-based domain, which binds to IL-17A and/or IL-17F.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 C.F.R. 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(f) or (g) prior art under 35 U.S.C. 103(a).
Claim 20 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hultberg et al. (WO 2010142551, 12/16/2010).
Hultberg discloses single variable domain (vhh) antibodies to receptors to cytokines of the IL-17 family (abstract, for example), which can be used for the prevention and treatment of IL-17 related diseases and disorders which are characterized by excessive and/or unwanted signalling mediated by a receptor for an interleukin of the IL-17 family (for example, caused by exaggerated levels, production, activity and/or sensitivity to interleukins of the IL-17 family) or by the pathway(s) in which a receptor for an interleukin of the IL-17 family is involved; for example, the antibodies of the invention are directed against the IL-17 receptors, in particular, they are antagonists of the IL-17 receptors and/or of the signalling that is mediated by IL-17A, IL- 17F and/or their receptors (page 5, last two paragraphs, for example). Additionally, Hultberg teaches a method of generating the VHH antibodies against the IL-17 receptors, wherein two llamas were immunized with 6 boosts of a cocktail of IL-17R and IL-17BR; blood was then collected from these animals for making phage libraries; the antibody clones were selected, and tested in competition assays with IL-17A (pages 221-228, Examples 1-6).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to make VHH antibodies against IL-17A and/or IL-17F by immunizing llamas with IL-17A and/or IL-17F, following the teachings of Hultberg. The person of ordinary skill in the art would have been motivated to do so for treating IL-17A/F mediated diseases, as both IL-17A/F and IL-17R are involved in the disease development, thus, antagonizing either one with a VHH antibody would block the IL-17A/F mediated signaling pathway; and reasonably would have expected success because Hultberg has demonstrated the success in making the llamas-derived VHH antibodies to IL-17R.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claim 20 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Adams et al. (US20100266609A1, 10/21/2010; provided by applicant), and further in view of Hamers et al. (US20030088074A1, 5/8/2003.
Adams discloses antibody molecules which bind IL-17A and IL-17F, wherein the antibodies of the invention include whole antibodies and functionally active fragments or derivatives thereof and may be, but are not limited to, monoclonal, multi-valent, multi-specific, humanized or chimeric antibodies, domain antibodies e.g. VH, VL, VHH, single chain antibodies, Fab fragments (abstract; page 2, [0012], and page 5, [0060], for example). Adams does not specifically mention that the domain antibodies or VHH are derived from camelid.
Hamers teaches that the heavy-chain antibodies, such as those derived from camel, and their fragments present clear advantages over other antibodies or fragments thereof derived from other animals; these are linked to the distinctive features of the heavy chain antibodies and in particular the novel fragments which can be produced by proteolytic cleavage within the hinge of these heavy-chain antibodies to generate the V HH and the (VHHh)2 fragments; the VHH domain of a heavy chain has distinct genetic entities which confer properties of solubility not found in VH fragments derived from conventional antibodies, which property, in addition to its small size and to the fact that the amino acid sequence of the framework region is very homologous to that of human, ensures a minimum of immunogenicity; and these properties would allow repetitive treatment with heavy chain VHH fragments for passive immunisation or antibody therapy (page 6, [0099]). Additionally, Hamers teaches a method of generating specific camel VHH fragments against tetanus toxoid, wherein a camel was immunized with the antigen, and a camel VHH library was generated and screed (pages 7-8, Example I).
It would have been obvious to the person of ordinary skill in the art at the time the invention was made to make VHH antibodies against IL-17A and/or IL-17F by immunizing a camel with IL-17A and/or IL-17F, following the teachings of Adams and Hamers. The person of ordinary skill in the art would have been motivated to do so for treating IL-17A/F mediated diseases, and for the advantages of VHH antibody as taught by Adams and Hamers; and reasonably would have expected success because Hamers has demonstrated the success in making the camel-derived VHH antibodies an antigen.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Conclusion:
No claim is allowed.
Advisory Information:
Any inquiry concerning this communication should be directed to Examiner DONG JIANG whose telephone number is 571-272-0872. The examiner can normally be reached on Monday - Friday from 9:30 AM to 7:00 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Vanessa Ford, can be reached on 571-272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DONG JIANG/
Primary Examiner, Art Unit 1674
11/10/25