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 .
DETAILED ACTION
Status of Application/Election/Restrictions
Claims 3 and 11 are canceled. Claims 1-2, 4-10 and 12-16 are pending in this application and under examination in this office action.
Specification
The disclosure is objected to because of the following informalities: The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p.2; p.15; p.21 of the amended specification filed 06/23/2023). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Appropriate correction is required.
Claim Objections
Claims 1-2 and 13-14 are objected to because of the following informalities:
i. Claims 1-2 depend from claim 4, which is not a preceding claim. A series of singular dependent claims is permissible in which a dependent claim refers to a preceding claim which, in turn, refers to another preceding claim.
A claim which depends from a dependent claim should not be separated by any claim which does not also depend from said dependent claim. It should be kept in mind that a dependent claim may refer to any preceding independent claim. In general, applicant's sequence will not be changed. See MPEP § 608.01(n). Appropriate correction is required.
ii. The spelling of “tumor” in claim 13 is incorrect. Appropriate correction is required.
iii. Claim 14 recites the limitation “The single-domain antibody moiety of claim 13…”. However, claim 13 was amended and is directed to a method for treatment. Appropriate correction is required.
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 2 and 13-16 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 pre-AIA the applicant regards as the invention.
Claims 2 and 13-16 are indefinite because:
i. Claim 2 recites the limitation "the N-terminal extracellular region " in lines 2-3 of the claim. There is insufficient antecedent basis for this limitation in the claim.
ii. Claim 13 recites the limitation "the treatment " in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim.
ii. Regarding claim 16, it is unclear whether the limitation “A human CCR8 (hCCR8) binder” recited in claim 16 means “a molecule binding to human CCR8” such as an antibody binding to human CCR8 antibody or “a human molecule binding to CCR8”, such as “a human antibody binding to CCR8”. Thus, the claim is indefinite. It is also unclear what the claimed human CCR8 binder is the CDR1-3 are not defined and vary. Since the metes and bounds cannot be determined, A skilled artisan cannot envision what CDR1-3 are and what human CCR8 binder are and included within the scope of the claim. Thus, the claim is indefinite. For examination purposes, the limitation is interpreted as “
iv. The rest of claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
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 1-2, 4-6, 9-10 and 12-16 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.
To provide adequate written description and evidence of possession of a claimed 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.
Claims 1-2, 4-10 and 12 are drawn to a single-domain antibody moiety that binds to human CCR8 (hCCR8), wherein the single-domain antibody moiety comprises CDR1-3, and wherein CDR3 is selected from the amino acid sequence of SEQ ID NO:3 or variants thereof having at least 80% identity to SEQ ID NO:3 or having 3, 2, or 1 amino acid difference with SEQ ID NO:3.
Claims 13-15 are drawn to a method for the treatment of a tumor in a subject, comprising administering to the subject the claimed single domain antibody moiety.
Claim 16 is drawn to a human CCR8 (hCCR8) binder, wherein the binder comprises CDRs:CDR1-3, wherein the CDRs are selected from the respective CDR1s, CDR2s and CDR3s comprised in SEQ ID NOs: 8 and 9, and wherein the CDRs defined by the Kabat, Chothia, AHo or IMGT information system.
The claims 1-2, 4-6, 9-10 and 12-15 encompass a genus of single-domain antibody moiety binding to human CCR8 (hCCR8), wherein the single-domain antibody moiety comprises CDR1-3 with no defined sequences for CDR1-2 and CDR3 comprising SEQ ID NO:3 or variant thereof. The claims 13-15 encompass using the claimed genus of single-domain antibody moiety binding to hCCR8 for treating a tumor including different forms of cancer. Claims 9-10 encompass a genus of cytotoxic moiety including inducing ADCC, CDC, ADCP, activating T-cells or cytotoxic payload. Claim 16 encompasses a genus of human CCR8 (hCCR8) binder comprising CDR1-3 selected from the respective CDR1s, CDR2s and CDR3s comprised in SEQ ID NOs: 8 and 9 and as defined by the Kabat, Chothia, AHo or IMGT information system.
Applicant has not disclosed sufficient species for the broad genus of single-domain antibody moiety comprising CDR1-3 with no defined sequences for CDR1-2 and CDR3 comprising SEQ ID NO:3 or variant thereof recited in claim 4, or variants of SEQ ID NOs: 1-3 for CDRs1-3 respectively recited in claim 5 or hCCR8 binder recited in claim 16. Applicant also has not disclosed sufficient species for using the claimed genus of single-domain antibody moiety for treating tumor or cancer.
The specification only describes the following VHH and VHH-Fc fusion proteins that bind to hCCR8 and non-blocking hCCR8 and their activities (see Examples 14-23 and figures 9-16):
Name SEQ ID NO: Fragments Non-blocking ADCC
VHH-69 10 VHH-69 + -
VHH-123 8 VHH-69(E1D,N55S,D65G) + -
VHH-124 9 VHH-69(E1D,N55K,D65G) + -
VHH-Fc-218 27 VHH-69-hIgG1-Fc + +
VHH-Fc-219 21 VHH-69-(GS)10-hIgG1-Fc + +
VHH-Fc-220 22 VHH-69-(GS)20-hIgG1-Fc + +
VHH-Fc-262 29 VHH124-hIgG1-Fc + +
VHH-Fc-264 26 VHH214-(GS)20-hIgG1-Fc + +
However, the claims are not limited to the VHH and VHH-Fc fusion proteins set forth above but also encompass structurally and functionally undefined single domain antibody moiety comprising CDR1-3 with no defined sequences for CDR1-2 and CDR3 comprising SEQ ID NO:3 or variant thereof and their use for treating a tumor including different types of cancer.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification, Applicant is in possession of VHH and VHH-Fc set forth above that bind to hCCR8 and without blocking hCCR8. Applicant is also in possession of the VHH-Fc fusion proteins with defined sequences set forth above including VHH-Fc-218, VHH-Fc-219, VHH-Fc-220, VHH-Fc-260 and VHH-Fc-264 that bind to hCCR8 and without blocking hCCR8 and possess ADCC cytotoxic activities.
However, Applicant is not in possession of other structurally and functionally undefined single-domain antibody moieties that bind to human CCR8 (hCCR8) comprising CDR1-3 with no defined sequences for CDR1-2 and CDR3 comprising SEQ ID NO:3 or variant thereof, or comprising variants of SEQ ID NOs: 1-3 for CDRs1-3 or the claimed genus of hCCR8) binder recited in claim 16. Applicant is also not in possession of using the claimed genus of single-domain antibody moieties that bind to human CCR8 (hCCR8) for treating a tumor including different types of cancer. Applicant is not in possession of using a genus of structurally and functionally undefined cytotoxic moiety for inducing ADCC, CDC, ADCP, activating T-cells or cytotoxic payload or using the claimed genus of single-domain antibody moieties with no defined structure and function for treating a tumor or cancer.
The claimed genus of single-domain antibody moiety recited in instant claims and the claimed genus of human CCR8 (hCCR8) binder recited in claim 16 are not limited to heavy chain variable domain (VHH) antibodies or VHH-Fc fusion proteins as shown in Examples but also encompass any single domain antibodies with no defined structure and function in view of p. 8-11 of the specification.
In addition, based on Applicant’s own admission, VHH-69 binding hCCR8 without blocking hCCR8 (Examples 15-23) or a mouse VHH (VHH-06) binding to mouse CCR8 (mCCR8) without blocking mCCR8 mouse does not have ADCC toxicity and cannot block mCCR8 Treg cells to reduce tumor size (see Examples 8-10). Only fusion proteins comprising VHH-69 fused to a human IgG1-Fc: VHH-Fc-218, VHH-Fc-219, VHH-Fc-220, VHH-Fc-262 and VHH-Fc-264 possess ADCC toxicity in HEK293 cells expressing hCCR8.
Further, it is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. MacCallum et al. (J. Mol. Biol.,1996; 262: 732-745) teaches that although CDR3 of the heavy and light chain dominates, a number of residues outside the standard CDR definitions make antigen contacts (see p. 733, right col) and non-contacting residues within the CDRs coincide with residues as important in defining canonical backbone conformations (see page 735, left col.). Pascalis et al. (The Journal of Immunology, 2002; 169: 3076-3084) teaches that grafting of the CDRs into a human framework was performed by grafting CDR residues and maintaining framework residues that were deemed essential for preserving the structural integrity of the antigen binding site (see page 3079, right col.) and that although abbreviated CDR residues were used in the constructs, some residues in all 6 CDRs were used for the constructs (see page 3080, left col.). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site because although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.; Casset et al., BBRC, 2003; 307: 198-205). Vajdos et al. (J. Mol. Biol. 2002; 320: 415-428) also teaches that antigen binding is primarily mediated by the CDRs more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations and in some cases framework residues also contact antigen (page 416, left col.). Holm et al. (Mol. Immunol., 2007; 44: 1075-1084) teaches that although residues in the CDR3 of the heavy chain were involved in antigen binding, unexpectedly a residue in CDR2 of the light chain was also involved (abstract). Chen et al. (J. Mol. Bio., 1999; 293: 865-881) teaches that the antigen binding site is almost entirely composed of residues from heavy chain CDRs, CDR-H1, H2, H3 (page 866). Wu et al. (J. Mol. Biol., 1999; 294:151-162) teaches that it is difficult to predict which framework residues serve a critical role in maintaining affinity and specificity due in part to the large conformational change in antibodies that accompany antigen binding (page 152 left col.) but certain residues have been identified as important for maintaining conformation.
It is also known in the art that a single amino acid change on a protein or molecule can abolish the binding ability or activity of the protein or molecule. For example, a substitution of lysine residue by glutamic acid at position 118 of acidic fibroblast growth factor results in a substantial loss of its biological activity including the binding ability to heparin and its receptor (Burgess et al. J of Cell Bio. 1990, 111:2129-2138). Although many amino acid substitutions are possible in any given protein, the position of where such amino acid substitutions can be made is critical for maintaining the function of a protein; i.e. only certain positions can tolerate conservative substitutions without changing the relationship of three dimensional structure and function of the protein (col 2, p. 1306, Bowie et al. Science, 1990, 247:1306-1310). Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would not immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active because conformation is dependent upon surrounding residues; i.e. substitution of non-essential residues can often destroy activity. In addition to a core determinant sequence, the protein-protein interaction also relies on the flanking or noncontiguous residues (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452). The optimal binding motif for a domain is not necessarily suitable for physiological or in vivo interaction. The predictive data always need to be validated by actual analyses in cells (see p. 445, the third column, second paragraph, Pawson et al. 2003, Science 300:445-452). Alaoui-lsmaili teaches that designing a mutein having predictable activities is difficult because of the complexity of the interactions between ligands and receptors (Alaoui-lsmaili et al., Cytokine Growth Factor Rev. 2009; 20:501-507). For example, given the complexity of BMP-BMP receptor interactions, it is difficult to design BMPs with improved affinity and/or specificity for one specific receptor. More importantly, predicting the in vivo biological activity of such altered BMPs remains a challenging undertaking (see p. 502, right col., 2th paragraph). Further, when multiple mutations are introduced, there is even less predictability because Guo et al. teaches that the effects of mutations on protein function are largely additive (see p. 9207, left col., 2th paragraph, Guo et al., PNAS 2004; 101:9205-9210). Moreover, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. USA 1982 Vol. 79: page 1979). Rudikoff et al teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function.
The specification provides no well-established structural and functional relationship or correlation between the claimed genus of single-domain antibody moieties with no defined sequences for CDR1-2 or comprising variants of SEQ ID NOs: 1-3 for CDRs1-3 or the claimed genus of hCCR8 binder recited in claim 16 and VHH-69 or VHH-Fc-218, VHH-Fc-219, VHH-Fc-220, VHH-Fc-262 and VHH-Fc-264 shown in Examples of the specification. Applicant fails to teach what structures/amino acid sequences are for the claimed genus of single-domain antibody moieties that bind to human CCR8 (hCCR8) comprising CDR1-3 with no defined sequences for CDR1-2 and CDR3 comprising SEQ ID NO:3 or variants thereof, or comprising variants of SEQ ID NOs: 1-3 for CDRs1-3 or the claimed genus of hCCR8 binder recited in claim 16 or using a genus of structurally and functionally undefined cytotoxic moiety for inducing ADCC, CDC, ADCP, activating T-cells or cytotoxic payload or using the claimed genus of single-domain antibody moieties with no defined structure and function for treating a tumor or cancer.
Neither the specification nor the prior art teaches what other structurally and functionally undefined variant ingle-domain antibody moieties or hCCR8 binders are and can possess the claimed biological binding properties as claimed or for treating a tumor. The specification provides no identification of any particular portion of the structure that must be conserved. The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of single-domain antibody moiety comprising CDR1-3 with no defined sequences for CDR1-2, or variants of SEQ ID NOs: 1-3 for CDRs1-3 respectively recited in claims 4-5 or hCCR8 binder recited in claim 16 or their use for treating tumor or cancer. There is no description of the conserved regions which are critical to the function of the claimed genus. There is no description of the sites at which variability may be tolerated and there is no information regarding the relation of the structure of other single-domain antibody moieties comprising CDR1-3 with no defined sequences for CDR1-2 and CDR3 comprising SEQ ID NO:3 or variant thereof recited in claim 4, or variants of SEQ ID NOs: 1-3 for CDRs1-3 respectively recited in claim 5 or hCCR8 binder recited in claim 16 to the function of VHH-69 or VHH-Fc-218, VHH-Fc-219, VHH-Fc-220, VHH-Fc-262 and VHH-Fc-264 shown in Examples of the specification.
Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to isolate and identify what other single-domain antibody moieties or hCCR8 binders containing structurally and functionally undefined sequences might be. Since the common characteristics/features of other single-domain antibody moieties or hCCR8 binders containing structurally and functionally undefined sequences are unknown, a skilled artisan cannot envision the functional correlations of the genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of single-domain antibody moieties or hCCR8 binders or their use for treating a tumor.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
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 chemical structure of the encompassed genus of single-domain antibody moieties or hCCR8 binders or their use for treating a tumor, 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. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 and Centocor v. Abbott, 636 F.3d1341 (Fed. Cir. 2011) and AbbVie v. Janssen, 759 F.3d 1285 (Fed. Cir.2014). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed single-domain antibody moiety, the claimed hCCR8 binder and the claimed method of treating a tumor using the claimed single domain antibody moiety have not met 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). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Conclusion
Allowable Subject Matter
Claim 7 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 1-2, 4-6, 8-10 and 12-16 are rejected.
Sequence alignment
SEQ ID NO:26(VHH-264) 1 DVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGK 60
SEQ ID NO:29(VHH-262) 1 DVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGK 60
SEQ ID NO:22(VHH-Fc-220) 1 EVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGN 60
SEQ ID NO:8(VHH-123) 1 DVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGS 60
SEQ ID NO:9(VHH-124) 1 DVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGK 60
SEQ ID NO:10(VHH-69) 1 EVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGN 60
SEQ ID NO:1(CDR1) 1 -------------------------GRTFTNYKSNYK----------------------- 12
SEQ ID NO:2(CDR2) 1 ------------------------------------------------------TDWTGX 6
SEQ ID NO:3(CDR3) ------------------------------------------------------------
SEQ ID NO:26(VHH-264) 61 SAIIANSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTTIGQYTYWGQGTLVTV 120
SEQ ID NO:29(VHH-262) 61 SAIIANSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTTIGQYTYWGQGTLVTV 120
SEQ ID NO:22(VHH-Fc-220) 61 SAIIANSVKDRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTTIGQYTYWGQGTLVTV 120
SEQ ID NO:8(VHH-123) 61 SAIIANSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTTIGQYTYWGQGTLVTV 120
SEQ ID NO:9(VHH-124) 61 SAIIANSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTTIGQYTYWGQGTLVTV 120
SEQ ID NO:10(VHH-69) 61 SAIIANSVKDRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTTIGQYTYWGQGTLVTV 120
SEQ ID NO:1(CDR1) ------------------------------------------------------------
SEQ ID NO:2(CDR2) 7 SA---------------------------------------------------------- 8
SEQ ID NO:3(CDR3) 1 ----------------------------------------AAGTTIGQYTY--------- 11
SEQ ID NO:34(CDR3) 1 ------------------------------------------GTTIGQYTY--------- 9
SEQ ID NO:26(VHH-264) 121 SSGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 180
SEQ ID NO:29(VHH-262) 121 SS--------------------DKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 160
SEQ ID NO:22(VHH-Fc-220) 121 SSGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPE 180
SEQ ID NO:8(VHH-123) 121 SS---------------------------------------------------------- 122
SEQ ID NO:9(VHH-124) 121 SS---------------------------------------------------------- 122
SEQ ID NO:10(VHH-69) 121 SS---------------------------------------------------------- 122
SEQ ID NO:26(VHH-264) 181 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 240
SEQ ID NO:29(VHH-262) 161 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 220
SEQ ID NO:22(VHH-Fc-220) 181 VTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKE 240
SEQ ID NO:26(VHH-264) 241 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA 300
SEQ ID NO:29(VHH-262) 221 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA 280
SEQ ID NO:22(VHH-Fc-220) 241 YKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIA 300
SEQ ID NO:26(VHH-264) 301 VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 360
SEQ ID NO:29(VHH-262) 281 VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 340
SEQ ID NO:22(VHH-Fc-220) 301 VEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ 360
SEQ ID NO:26(VHH-264) 361 KSLSLSPG 368
SEQ ID NO:29(VHH-262) 341 KSLSLSPG 348
SEQ ID NO:22(VHH-Fc-220) 361 KSLSLSPG 368
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
WO2018220235 teaches an anti-MMP13 VHH comprising SEQ ID NO:10, which is 74.3% identical to instant SEQ ID NO:8, 73.9% identical to instant SEQ ID NO:9 or an anti-MMP13 construct (40E09-517A01 clone 71) comprising SEQ ID 163, which is 73.0% identical to instant SEQ ID NO:10 (see the sequence alignment below).
SEQ ID NO:8
WO2018220235
BFW74884
ID BFW74884 standard; protein; 129 AA.
XX
AC BFW74884;
XX
DT 24-JAN-2019 (first entry)
XX
DE Anti-MMP13 immunoglobulin single variable domain VHH region, SEQ 10.
XX
KW MMP13; Metalloprotease-13; achondroplasia; antiarthritic;
KW antibody production; antibody therapy; antiinflammatory; arthritis;
KW chondrodystrophy; collagenase; cytostatic; degeneration; diagnostic test;
KW dysplasia; gout; growth-disorder-gen.; heavy chain variable region;
KW hernia; immuno-diagnosis; joint disease; matrix metalloproteinase 13;
KW musculoskeletal-gen.; nanobody; osteoarthritis; osteochondritis;
KW osteopathic; polychondritis; prophylactic to disease;
KW psoriatic arthritis; rheumatoid arthritis; single domain antibody;
KW therapeutic; vulnerary.
XX
OS Camelidae.
XX
CC PN WO2018220235-A1.
XX
CC PD 06-DEC-2018.
XX
CC PF 04-JUN-2018; 2018WO-EP064667.
XX
PR 02-JUN-2017; 2017EP-00174402.
XX
CC PA (MERE ) MERCK PATENT GMBH.
CC PA (ABLY ) ABLYNX NV.
XX
CC PI Descamps F, Beste G, Hermans G, Guehring H, Toleikis L, Ladel C;
XX
DR WPI; 2018-96946V/01.
XX
CC PT Polypeptide comprises one immunoglobulin single variable domain binding
CC PT matrix metalloproteinase, where matrix metalloproteinase is chosen from
CC PT the group consisting of collagenase, matrix metalloproteinase-8, matrix
CC PT metalloproteinase-l.
XX
CC PS Claim 43; SEQ ID NO 10; 122pp; English.
XX
CC The present invention relates to a novel polypeptide useful for treating
CC or preventing matrix metalloproteinase (MMP) 13 associated diseases or
CC disorders. The polypeptide comprises one immunoglobulin single variable
CC domain (ISVD) binding to matrix metalloproteinase, where matrix
CC metalloproteinase is selected from MMP13 (collagenase), MMP8
CC (collagenase), MMP1 (collagenase), MMP19 and MMP20 (enamelysin). The
CC invention further provides: a method for treating, preventing or
CC diagnosing diseases or disorders and its symptoms such as arthropathies
CC and chondrodystrophies, arthritic diseases includes osteoarthritis,
CC rheumatoid arthritis, gouty arthritis, psoriatic arthritis, traumatic
CC rupture or detachment, achondroplasia, costochondritis,
CC Spondyloepimetaphyseal dysplasia, spinal disc herniation, lumbar disk
CC degeneration disease, degenerative joint disease, and relapsing
CC polychondritis, osteochondritis dissecans and aggrecanopathies by
CC administering the novel polypeptide; and a method for preparing the novel
CC polypeptide. The present sequence represents an anti-MMP13 ISVD heavy
CC chain variable region (VHH), which is used in the invention for treating
CC or preventing diseases or disorders associated with MMP13. Note: SEQ ID
CC 125 is mentioned in claim 40 but no corresponding sequence is provided in
CC the patent.
XX
SQ Sequence 129 AA;
Query Match 74.3%; Score 476.5; Length 129;
Best Local Similarity 70.7%;
Matches 94; Conservative 6; Mismatches 18; Indels 15; Gaps 2;
Qy 1 DVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGS 60
|||||||||||||||||||||| |||||| |:| | |||||||| | || |:|
Db 1 DVQLVESGGGLVQPGGSLRLSCAASGRTF----SSYAMGWFRQAPGKEREFVAAISWSGG 56
Qy 61 SAIIANSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTT-----------IGQY 109
| |:||||||||||||:||||||||||||||||||||| | :|:|
Db 57 STYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCTAALAVYGPNRYRYGPVGEY 116
Qy 110 TYWGQGTLVTVSS 122
||||||||||||
Db 117 NYWGQGTLVTVSS 129
SEQ ID NO:9
BFW74884
ID BFW74884 standard; protein; 129 AA.
XX
AC BFW74884;
XX
DT 24-JAN-2019 (first entry)
XX
DE Anti-MMP13 immunoglobulin single variable domain VHH region, SEQ 10.
XX
KW MMP13; Metalloprotease-13; achondroplasia; antiarthritic;
KW antibody production; antibody therapy; antiinflammatory; arthritis;
KW chondrodystrophy; collagenase; cytostatic; degeneration; diagnostic test;
KW dysplasia; gout; growth-disorder-gen.; heavy chain variable region;
KW hernia; immuno-diagnosis; joint disease; matrix metalloproteinase 13;
KW musculoskeletal-gen.; nanobody; osteoarthritis; osteochondritis;
KW osteopathic; polychondritis; prophylactic to disease;
KW psoriatic arthritis; rheumatoid arthritis; single domain antibody;
KW therapeutic; vulnerary.
XX
OS Camelidae.
XX
CC PN WO2018220235-A1.
XX
CC PD 06-DEC-2018.
XX
CC PF 04-JUN-2018; 2018WO-EP064667.
XX
PR 02-JUN-2017; 2017EP-00174402.
XX
CC PA (MERE ) MERCK PATENT GMBH.
CC PA (ABLY ) ABLYNX NV.
XX
CC PI Descamps F, Beste G, Hermans G, Guehring H, Toleikis L, Ladel C;
XX
DR WPI; 2018-96946V/01.
XX
CC PT Polypeptide comprises one immunoglobulin single variable domain binding
CC PT matrix metalloproteinase, where matrix metalloproteinase is chosen from
CC PT the group consisting of collagenase, matrix metalloproteinase-8, matrix
CC PT metalloproteinase-l.
XX
CC PS Claim 43; SEQ ID NO 10; 122pp; English.
XX
CC The present invention relates to a novel polypeptide useful for treating
CC or preventing matrix metalloproteinase (MMP) 13 associated diseases or
CC disorders. The polypeptide comprises one immunoglobulin single variable
CC domain (ISVD) binding to matrix metalloproteinase, where matrix
CC metalloproteinase is selected from MMP13 (collagenase), MMP8
CC (collagenase), MMP1 (collagenase), MMP19 and MMP20 (enamelysin). The
CC invention further provides: a method for treating, preventing or
CC diagnosing diseases or disorders and its symptoms such as arthropathies
CC and chondrodystrophies, arthritic diseases includes osteoarthritis,
CC rheumatoid arthritis, gouty arthritis, psoriatic arthritis, traumatic
CC rupture or detachment, achondroplasia, costochondritis,
CC Spondyloepimetaphyseal dysplasia, spinal disc herniation, lumbar disk
CC degeneration disease, degenerative joint disease, and relapsing
CC polychondritis, osteochondritis dissecans and aggrecanopathies by
CC administering the novel polypeptide; and a method for preparing the novel
CC polypeptide. The present sequence represents an anti-MMP13 ISVD heavy
CC chain variable region (VHH), which is used in the invention for treating
CC or preventing diseases or disorders associated with MMP13. Note: SEQ ID
CC 125 is mentioned in claim 40 but no corresponding sequence is provided in
CC the patent.
XX
SQ Sequence 129 AA;
Query Match 73.9%; Score 474.5; Length 129;
Best Local Similarity 70.7%;
Matches 94; Conservative 6; Mismatches 18; Indels 15; Gaps 2;
Qy 1 DVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGK 60
|||||||||||||||||||||| |||||| |:| | |||||||| | || |:|
Db 1 DVQLVESGGGLVQPGGSLRLSCAASGRTF----SSYAMGWFRQAPGKEREFVAAISWSGG 56
Qy 61 SAIIANSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTT-----------IGQY 109
| |:||||||||||||:||||||||||||||||||||| | :|:|
Db 57 STYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCTAALAVYGPNRYRYGPVGEY 116
Qy 110 TYWGQGTLVTVSS 122
||||||||||||
Db 117 NYWGQGTLVTVSS 129
SEQ ID NO:10
BFW75036
ID BFW75036 standard; protein; 278 AA.
XX
AC BFW75036;
XX
DT 24-JAN-2019 (first entry)
XX
DE Anti-MMP13 construct (40E09-517A01 clone 71), SEQ ID 163.
XX
KW MMP13; Metalloprotease-13; achondroplasia; antiarthritic;
KW antibody production; antibody therapy; antiinflammatory; arthritis;
KW chondrodystrophy; collagenase; cytostatic; degeneration; diagnostic test;
KW dysplasia; gout; growth-disorder-gen.; heavy chain variable region;
KW hernia; immuno-diagnosis; joint disease; matrix metalloproteinase 13;
KW musculoskeletal-gen.; nanobody; osteoarthritis; osteochondritis;
KW osteopathic; polychondritis; prophylactic to disease;
KW psoriatic arthritis; rheumatoid arthritis; single domain antibody;
KW therapeutic; vulnerary.
XX
OS Camelidae.
OS Synthetic.
XX
CC PN WO2018220235-A1.
XX
CC PD 06-DEC-2018.
XX
CC PF 04-JUN-2018; 2018WO-EP064667.
XX
PR 02-JUN-2017; 2017EP-00174402.
XX
CC PA (MERE ) MERCK PATENT GMBH.
CC PA (ABLY ) ABLYNX NV.
XX
CC PI Descamps F, Beste G, Hermans G, Guehring H, Toleikis L, Ladel C;
XX
DR WPI; 2018-96946V/01.
XX
CC PT Polypeptide comprises one immunoglobulin single variable domain binding
CC PT matrix metalloproteinase, where matrix metalloproteinase is chosen from
CC PT the group consisting of collagenase, matrix metalloproteinase-8, matrix
CC PT metalloproteinase-l.
XX
CC PS Claim 43; SEQ ID NO 163; 122pp; English.
XX
CC The present invention relates to a novel polypeptide useful for treating
CC or preventing matrix metalloproteinase (MMP) 13 associated diseases or
CC disorders. The polypeptide comprises one immunoglobulin single variable
CC domain (ISVD) binding to matrix metalloproteinase, where matrix
CC metalloproteinase is selected from MMP13 (collagenase), MMP8
CC (collagenase), MMP1 (collagenase), MMP19 and MMP20 (enamelysin). The
CC invention further provides: a method for treating, preventing or
CC diagnosing diseases or disorders and its symptoms such as arthropathies
CC and chondrodystrophies, arthritic diseases includes osteoarthritis,
CC rheumatoid arthritis, gouty arthritis, psoriatic arthritis, traumatic
CC rupture or detachment, achondroplasia, costochondritis,
CC Spondyloepimetaphyseal dysplasia, spinal disc herniation, lumbar disk
CC degeneration disease, degenerative joint disease, and relapsing
CC polychondritis, osteochondritis dissecans and aggrecanopathies by
CC administering the novel polypeptide; and a method for preparing the novel
CC polypeptide. The present sequence represents an anti-MMP13 construct
CC comprising two anti-MMP13 ISVD heavy chain variable regions (VHHs) linked
CC via a linker, which is used in the invention for treating or preventing
CC diseases or disorders associated with MMP13. Note: SEQ ID 125 is
CC mentioned in claim 40 but no corresponding sequence is provided in the
CC patent.
XX
SQ Sequence 278 AA;
Query Match 73.0%; Score 468.5; Length 278;
Best Local Similarity 69.9%;
Matches 93; Conservative 6; Mismatches 19; Indels 15; Gaps 2;
Qy 1 EVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGN 60
|||||||||||||||||||||| |||||| |:| | |||||||| | || |:|
Db 150 EVQLVESGGGLVQPGGSLRLSCAASGRTF----SSYAMGWFRQAPGKEREFVAAISWSGG 205
Qy 61 SAIIANSVKDRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAGTT-----------IGQY 109
| |:||| ||||||||:||||||||||||||||||||| | :|:|
Db 206 STYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAVYYCTAALAVYGPNRYRYGPVGEY 265
Qy 110 TYWGQGTLVTVSS 122
||||||||||||
Db 266 NYWGQGTLVTVSS 278
WO2021156490 teaches a humanized anti-S protein VH comprising SEQ ID NO:11, which is 73.4% identical to instant SEQ ID NO:10 (see the sequence alignment below).
SEQ ID NO:10
BJT36748
ID BJT36748 standard; protein; 125 AA.
XX
AC BJT36748;
XX
DT 16-SEP-2021 (first entry)
XX
DE Humanized anti-S protein antibody heavy chain variable region, SEQ ID 11.
XX
KW S protein; antibody therapy; coronavirus infection; diagnostic test;
KW heavy chain variable region; humanized antibody; imaging;
KW immuno-diagnosis; immunoassay; mutein; prophylactic to disease;
KW protein detection; respiratory-gen.; sars coronavirus infection;
KW spike protein; therapeutic; virucide; virus-like particle.
XX
OS Lama glama.
OS Synthetic.
XX
CC PN WO2021156490-A2.
XX
CC PD 12-AUG-2021.
XX
CC PF 05-FEB-2021; 2021WO-EP052885.
XX
PR 06-FEB-2020; 2020US-0971013P.
PR 12-MAR-2020; 2020US-0988610P.
PR 18-MAR-2020; 2020US-0991408P.
PR 19-JUN-2020; 2020US-0041240P.
PR 25-SEP-2020; 2020WO-EP077004.
PR 23-DEC-2020; 2020GB-00020508.
PR 13-JAN-2021; 2021EP-00151356.
XX
CC PA (VIBV ) VIB VZW.
CC PA (UGNT ) UNIV GENT.
CC PA (USSH ) US DEPT HEALTH & HUMAN SERVICES.
CC PA (TEXA ) UNIV TEXAS SYSTEM.
CC PA (EXEV-) EXEVIR BIO BV.
CC PA (DARC ) DARTMOUTH COLLEGE.
CC PA (UYLN ) UNIV KATHOLIEKE LEUVEN KU LEUVEN R & D.
CC PA (ULBR ) UNIV VRIJE BRUSSEL.
XX
CC PI Schepens B, Saelens X, Callewaert N, De Vlieger D, Van Schie L;
CC PI Nerinckx W, Roose K, Van Breedam W, Eeckhaut H, Fijalkowska D;
CC PI Lonigro C, De Cae S, Dombrecht B, Stortelers C, Neyts J, Delang L;
CC PI Kaptein S, Duarte Da Rocha Pereira J, Graham B, Mclellan J, Wrapp D;
CC PI Remaut H;
XX
DR WPI; 2021-93399V/071.
XX
CC PT Binding agent specifically binding corona virus spike protein as
CC PT medicament and diagnostic, in in-vivo imaging, prophylactic or
CC PT therapeutic treatment with coronavirus infection, comprises amino acid
CC PT residues Leu355, Tyr356 and Ser358.
XX
CC PS Claim 8; SEQ ID NO 11; 220pp; English.
XX
CC The present invention relates to a novel binding agent specifically
CC binding to the coronavirus spike protein, useful in preparing a
CC medicament for treating and preventing coronavirus infection. The binding
CC agent specifically binds to the coronavirus spike protein comprising
CC amino acid residues L355, Y356, S358, S362, T363, F364, K365, C366 and
CC Y494 of BJT36761. The invention also provides: a nucleic acid molecule
CC encoding the binding agent; a recombinant vector comprising the nucleic
CC acid molecule; a complex comprising a receptor binding domain of SARS-
CC Corona virus encoding nucleotides of BJT36762 and BJT36763 and the
CC binding agent; a host cell comprising the binding agent, nucleic acid
CC molecule, recombinant vector or complex; a pharmaceutical composition
CC comprising the binding agent, nucleic acid molecule or recombinant vector
CC ; and the use of the binding agent for (a) detecting a viral particle or
CC a viral spike protein from a virus selected from the group of viruses
CC belonging to clade 1a, 1b, 2 and/or 3 of bat SARS-related sarbecoviruses,
CC and SARS-Cov-2, GD-Pangolin, RaTG13, WIV1, LYRall, RsSHCOM, Rs7327, SARS-
CC CoV-1, Rs4231, Rs4084, Rp3, HKU3-1 or BM48-31 viruses, and (b) diagnosing
CC sarbecoviruses such as SARS-CoV-2 viruses, and in-vivo imaging purposes.
XX
SQ Sequence 125 AA;
Query Match 73.4%; Score 471.5; Length 125;
Best Local Similarity 74.4%;
Matches 96; Conservative 4; Mismatches 18; Indels 11; Gaps 3;
Qy 1 EVQLVESGGGLVQPGGSLRLSCTASGRTFTNYKSNYKMAWFRQAPGKARAFVGRTDWTGN 60
|||||||||||||||||||||| |||||| | | | |||||||| | || |:|
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGRTF----SEYAMGWFRQAPGKEREFVATISWSGG 56
Qy 61 SAIIANSVKDRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAA---GTTIGQ----YTYWG 113
| |:||| |||||||||||||||||||||||||||||||| || : : | |||
Db 57 STYYADSVKGRFTISRDNAKNTVYLQMNSLRPEDTAVYYCAAAGLGTVVSEWDYDYDYWG 116
Qy 114 QGTLVTVSS 122
|||||||||
Db 117 QGTLVTVSS 125
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached Monday-Thursday, 7:00am-5:00pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker can be reached at 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Chang-Yu Wang
April 1, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675