DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09 December 2025 has been entered.
Claim Status
Claims 9, 12-20, and 29-30 are cancelled. Claims 1-8, 10-11, 21-28, and 31-36 as filed on 09 December 2025 are pending. Claim 28 is withdrawn. Claims 1-8, 10-11, 21-27, and 31-36 are under examination.
Rejection Maintained
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8, 10-11, 21-28, and 31-36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 1, 4, and 11 contain the parenthetical “Kabat numbering”, this renders the claim and claims dependent on it indefinite because it is unclear whether the limitations within the parentheticals is a preferred example, and therefore not limiting, or is part of the claimed invention.
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.
Claims 1-8, 10-11, 21-27, and 31-36 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.
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
Scope of the Claimed Genus
The claims are to a ligand-binding molecule wherein the ligand-binding molecule comprises a single-domain antibody that is a VHH or a single-domain VH antibody and can bind to a ligand and has at least one protease cleavage site introduced. The molecule of the claims is capable of binding its ligand target and when the cleavage site is cleaved the single-domain antibody is attenuated compared to when the protease cleavage site is not cleaved.
Claims 1 and 11 requires the cleavage site is introduced into one or more of the following sites where the position it is introduced based on kabat numbering: amino acid 12 to 13; amino acid 13 to 14; amino acid 14 to 15; amino acid 15 to 16; and amino acid 16 to 17.
Claim 4 requires the cleavage site is introduced based into one or more sites based on kabat numbering: from amino acid 7 to 17; 12 to 17; 40 to 47; 73 to 79, 83 to 89; and 101 to 113.
Claim 5 limits the protease to a cancer tissue specific protease or inflammatory tissue specific protease.
Claim 6 limits one of the proteases is at least one of the listed: matriptase, urokinase, and metalloprotease.
Claim 7 limits that the one or more protease sequences is one set forth in SEQ ID NO: 2 to 82 and 170 to 925.
These sequences have lengths including 4 amino acids to 18 amino acids.
Claim 8 is limited to the ligand being released from the ligand-binding molecule when the cleavage site or the protease cleavage sequence is cleaved.
Claim 10 limits the single-domain antibody has a neutralizing activity for the ligand wherein the ligand is a cytokine, chemokine or IL-6R, PD-1, IL-6, IL-12, or CXCL10.
Claims 31-33 is limited to the ligand being IL-6R.
Claim 34-36 is limited to the ligand being PD-1.
None of the claims provide the sequences of the single-domain antibody.
Only claim 7 limits the length of the cleavage sequence and that is to sequences up to 18 amino acids.
State of the Relevant Art
It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (Of Record)(see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu et al. (Antibodies 2019 8, 55, 1-80) (Of Record) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Single domain VHH antibodies are separate from individual VH or VL domains in an antibody. Wagner HJ et al. (Int J Mol Sci. 2018 19(11): 3444) (PTO-892) taught in the context of nanobodies®, universal scaffolds have been identified, enabling the generation of robust or humanized VHH variants but, this strategy has only been applied to graft CDRs to acceptor frames obtained from animals of the same taxonomic family (page 2, last paragraph). Wagner taught the design of nanobody grafts with CDRs derived from conventional antibodies requires careful consideration, because both the heavy and light chain variable domain (VH and VL) form the antigen binding site and are involved in the recognition of the antigenic epitope (page 2, last paragraph). Furthermore, the framework plays an important role in CDR conformation and orientation and distinct framework residues often contribute directly to antigen binding (page 2, last paragraph).
Additionally, the prior art has taught single variable domains from species with VH and VL antibody pairing is distinct from other species with single domain only antibodies. (Holliger et al. (Nature Biotechnology 2005 23 1126–1136)) (PTO-892). Holliger taught despite early excitement concerning the functional activity of single variable heavy domain antibodies, these antibody fragments rarely retained the affinity of the parent antibody and were also poorly soluble and often prone to aggregation (page 1127, left to right column bridging paragraph). Holliger taught while high affinity single variable like domain antibodies are present in camelid, as VhH, and shark, as V-NAR, domains, these single domain antibodies are structurally different, wherein each display long surface loops, often larger than for conventional murine and human antibodies, and are able to penetrate cavities in target antigens, such as enzyme active sites (for example, lysozyme) and canyons in viral and infectious disease biomarkers (page 1127, left to right column bridging paragraph). Holliger taught the structural changes are shown in Fig. 2, wherein superimposition of a human VH domain (Fig. 2b) and a single domain V-NAR(Fig. 2c) has a vastly different CDR3 that does not overlap structurally (Fig. 2d). Holliger taught unlike mouse VH domains, camelid VhH and shark V-NAR domains are in general soluble and can be produced as stable in vitro targeting reagents (page 1127, right column, second paragraph). Holliger did not describe single domain VL antibodies as successful. Thus, single-domain antibodies are not generally only a VH or VL and antibodies and require both the VH and VL, which are distinct from VHH.
The CDR3 of a nanobody varies in length from 3 to -28 amino acids increasing the potential interaction surface with target antigens. This compensate for the lack of VL in the nanobody creating distinct orientation of nanobodies when they bind their targets when compared to conventional antibodies (Page 2 in col 2 in last paragraph, page 3 in col 1 in lines 1-9). VL single-domain antibodies of VH or VL domains require careful re-engineering as they are prone to aggregation and do not retain the affinity of the parental antibody (Robert & Wark. Archives of Biochemistry and Biophysics. 526(2):132-138 (2012)) (Of Record).
The insertion of cleavage sequences to single-domain antibodies would change the tertiary structure.
The framework regions of VHH provide structure which impact VHH binding activity. A VHH contains four framework regions with amino acids in frameworks 1-3 that are highly conserved and impact the structure and binding activity of the VHH.
(Noёl et. al. Biochimie. 131:11-19 (2016) (PTO-892) (Abstract and Figures 1-2, page 14 in col 1 in par 1 into par 2, and page 17 in col 2 in par 1). Noёl further teaches framework 1 comprises 23 amino acids, framework 2 comprises 12 amino acids, framework 3 comprises 32 amino acids, and framework 4 comprises 9 amino acids (Figures 2 and 4-5).
The CDRs of the VHH interact with framework sequences. These interactions would vary between CDR sequences and changes to the framework sequences would change these interactions resulting in changes to the structure and activity of the VHH (Rouet et. al. Journal of Biological Chemistry. 290(198):11905-11917 (2015) (PTO-892) (Abstract, Figures 5-7). Rouet further teaches that variation in the CDR sequences change the stability of VHH when humanizing a VHH so a consensus framework region of a VHH with variation to the CDRs, as allowed by the claims, would have varying activity as an antibody (page 11915 in col 1 in par 2-4).
Summary of Species Disclosed in the original specification
Applicant discloses the binding of 2 ligands: IL-6R and PD-1. Applicant discloses a single-domain antibody that binds IL-6R (instant SEQ ID NO: 120) and discloses its function in the instant application with only protease cleavage sequences (examples 5-6) wherein the protease cleavage sequences are inserted between amino acids 12 and 13, 13 and 14, 14 and 15, 15 and 16, and 16 and 17 of the single-domain antibody based on Kabat numbering (Table 2). These ligand-binding molecules are represented by instant SEQ ID NO: 123-127.
Applicant further discloses a single-domain antibody that binds PD1 in a molecule comprising a protease cleavage sight introduced. Applicant discloses 4 molecules in Table 7 of instant SEQ ID NO: 164-167. Applicant has not disclosed the insertion sites but they are not all of insertion sites of the instant claims.
Applicant shows two ligand binding antibodies and shows 5 anti-IL6R molecules and 4 anti-PD1 molecules comprising that maintain function with a protease cleavage inserted.
The insertion of cleavage sequences to single-domain antibodies would change the tertiary structure. Without knowing the antibody
Are the disclosed species representative of the claimed genus?
MPEP § 2163 states that 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 specification discloses 9 ligand-binding molecules of the instant claims.
Given the variability encompassed by the genus of any single-domain antibody and any cleavage protease sequence inserted at any point in the single-domain antibody or a broadly described protein of any type is not represented by 9 species. Therefore, the specification disclosed species cannot be considered representative of the genus.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity.
The applicant has not provided a shared structure either in terms of the form of the ligand-binding domain as each VHH CDRs provide its binding activity.
The insertion of protease sequences which would vary in length into framework regions would impact the ligand-binding molecule and the changes would be unpredictable varying based on location within the framework sequence of introduction, the length of the cleavage sequence being introduced, and the CDRs of the VHH which would be impacted by their movement within the sequence by the introduction and by what amino acids they would or would not now interact with.
No structure/function correlation is identified.
Conclusion:
In summary; the framework and CDRs of a VHH impacts its binding activity. The applicant does not limit the length of the cleavage sequences to be introduced. But the applicant does explicitly teach sequences of 18 amino acids in length, this is longer than framework 2 and 4 of the VHH. One of skill in the art would not be able to predict which CDR combinations would maintain binding activity with the varied cleavage sequences of the claims at the different positions of insertion of the claims. The introduction of a varied amino acid sequence of unknown length into the framework of a VHH would change its structure and activity in unpredictable ways.
For all of the reasons presented above, one of skill in the art would not know which of the countless other molecules encompassed by the claims that meet the highly general structural requirements of the claims would also possess the required functional activity. Therefore, the skilled artisan would not reasonably conclude that the inventors had full possession of molecules as broadly claimed at the time the application was filed.
Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, applicant was not in possession of the invention as claimed.
Rejection Maintained
Double Patenting
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.
Claims 1-8, 11, and 21-27 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6, and 8-22 of copending Application No. 17/615,633 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 1-7, reference application recites a polypeptide comprising a single-domain antibody that binds a ligand and a protease cleavage sequence wherein the binding of the single-domain antibody is attenuated when the cleavage site is cleaved (claims 1, 6, and 8-9). The reference application recites the cleavage sequences are in positions spanning fourth to fifteenth amino acids positions which would include the positions of the instant claims. The reference application recites the protease is matriptase or urokinase (claim 4) which cleaves a cleavage sequence of instant claim 7.
Regarding claim 8, reference application recites that the ligand is released from the ligand-binding molecule in a state where the cleave sire or protease cleavage sequence is cleaved (claims 6 and 9-10).
Regarding claims 13-14, reference application recites the molecule fused to the ligand (claim 11).
Regarding claim 15, reference application recites the fused molecule and ligand in a pharmaceutical composition (claims 12-13).
Regarding claims 16-18 and 21-27, the reference application recites a polynucleotide encoding the polypeptide, in a vector, and in a host cell (claims 14 and 16-121). Reference application recites a method of producing using a host cells comprising the molecule with and without the ligand (claims 18 and 22). The reference application recites a fusion of the ligand and the ligand-binding molecule (claim 11).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 4, 10 and 31-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 and 16-22 of copending Application No. 17/615,633 (reference application) in view of West (WO 2014/052462 A2) (IDS 04/14/2021 FP27).
The recitations of the application from the previous anticipatory style double patenting rejection are incorporated here in full.
Regarding claims 1 and 4, reference application recites a polypeptide comprising a single-domain antibody that binds a ligand and a protease cleavage sequence wherein the binding of the single-domain antibody is attenuated when the cleavage site is cleaved (claims 1, 6, and 8-9). The reference application recites the cleavage sequences are in positions spanning fourth to fifteenth amino acids positions which would include the positions of the instant claims. The reference application recites the protease is matriptase or urokinase (claim 4) which cleaves a cleavage sequence of instant claim 7.
The reference application recites the molecule fused to the ligand that it binds (claim 11).
The reference application does not recite the single-domain antibody has a neutralizing activity for the ligand or that the ligand is IL-6R.
These deficiencies are filled by West.
West teaches an activatable antibody that is part of a polypeptide that comprises an antibody that binds IL-6R, a protease cleavage sequence wherein the cleavage by a protease changes the activity of the antibody (abstract). West teaches the use of antibodies that neutralize activity for IL-6R ([000470]). West further teaches the use of single domain antibodies including ones that are VH or VL (claims 1 and 12).
It would have been obvious to one of ordinary skill in the art to substitute the single-domain antibody in the fusion of the reference application which comprises a generic single-domain antibody, a protease sequence, and the ligand that the single-domain antibody binds with the specific single-domain antibodies taught by West which bind IL-6R and the known ligand IL-6R. West teaches a protease cleavage activatable antibody that is a single-domain antibody that binds IL-6R. One of ordinary skill in the art would have been motivated to take the recited general single-domain antibody of the reference application with the specific types of single-domain antibodies that have inhibitory function of West as West teaches they are functional as antibodies under regulation by protease cleavage for use in treatment of human subjects. There would have been a reasonable expectation of success because the reference application and West are both working with the protease cleavage regulation of single-domain antibodies activity.
This is a provisional nonstatutory double patenting rejection.
Claims 1 and 34-36 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 and 16-22 of copending Application No. 17/615,633 (reference application) in view of Shen CN107814845A (PTO-892)
The recitations of the application from the previous anticipatory style double patenting rejection are incorporated here in full.
Regarding claim 1, the reference application recites a polypeptide comprising a single-domain antibody that binds a ligand and a protease cleavage sequence wherein the binding of the single-domain antibody is attenuated when the cleavage site is cleaved (claims 1, 6, and 8-9). The reference application recites the cleavage sequences are in positions spanning fourth to fifteenth amino acids positions which would include the positions of the instant claims. The reference application recites the protease is matriptase or urokinase (claim 4) which cleaves a cleavage sequence of instant claim 7.
The reference application recites the molecule fused to the ligand that it binds (claim 11).
The reference application does not recite the single-domain antibody has a neutralizing activity for the ligand or that the ligand is PD-1.
These deficiencies are filled by Shen.
Shen teaches single domain antibodies, VHH, that bind PD-1 that block PD-1 binding to PD-L1 (abstract and claims 1-9). Shen teaches these VHH are for use in a method of treating tumors (claim 10).
Shen teaches the antibody fused to additional elements (page 8 in par 9). Shen teaches the framework and CDR sequences of the VHH that binds PD-1 (page 4 in pars 4-5).
Shen further teaches PD-1 including its size and the nature of the polypeptide (page 3 in par 5).
It would have been obvious at the time the application was filed to to substitute the single-domain antibody in the fusion of the reference application which comprises a generic single-domain antibody, a protease sequence, and the ligand that the single-domain antibody binds with the specific single-domain antibodies taught by Shen which bind PD-1 the known ligand PD-1. The reference claims are to a fusion polypeptide comprising a VHH that binds a target of interest, the ligand that VHH binds, and a cleavage sequence. One of skill in the art would have been motivated to substitute the generic ligand target of the reference claims with PD-1 to produce a ligand-binding molecule that can be used in treatment of cancer. There would have been a reasonable expectation of success as the reference claims recite the VHHs as generic and interchangeable.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No Claims Allowable.
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/F.E./Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643