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 .
Response to Amendments
Applicant’s remarks and amendments to the claims received 11/24/2025 have been acknowledged. Claim 1 has been canceled. Claims 5, 8, 9, 12, 17, 27, 28, 31, 33, and 34 have been amended. The amendments to the claims overcome rejections previously set forth under 35 USC 112(a) written description.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/24/2025 has been entered.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 26, 33 and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Verdonck et al (US20150218281A1, of record), hereinafter Verdonck, in view of Totsuka et al (Totsuka, T et al. American journal of physiology. Gastrointestinal and liver physiology vol. 284,4 (2003): G595-603), hereinafter Totsuka, and Beirnaert (US20140335101A1, of record).
Verdonck teaches multi-specific and/or multi-valent polypeptide constructs comprising at least one nanobody that specifically binds to OX40L and one or more other nanobodies directed against targets other than OX40L, optionally linked via one or more suitable linkers, such as peptidic linkers, wherein polypeptides having two or more amino acid sequences that target OX40L will have higher avidity for OX40L (see Abstract, Summary of Invention, Claims, Para. 0031, 0035, 0040, 0046, 0291, 0292, and 0377). The linker may be amino acid sequences of between 1 and 50, preferably between 1 and 30, such as between 1 and 10 amino acid residues (Para. 0656). The polypeptides can have the sequence of SEQ ID NOs: 202 to 205 each of which is more than 95% identical to either SEQ ID NO: 2 or SEQ ID NO: 3 of the instant claims and fully comprise the CDRs of SEQ ID NOs: 7, 10, and 13 of the instant claims (Table A2). In some embodiments, the multi-specific polypeptides comprise at least one nanobody that provides for an increased half-life, such as nanobodies against human serum albumin (Para. 0673). The multi-specific/multi-valent polypeptide fusion proteins comprise a nanobody fused both at its amino (N)-terminal end and at its carboxy (C)- terminal end to at least one other amino acid sequence such as another nanobody (Para. 0650). Further disclosed are compositions comprising at least one polypeptide (or nucleotide encoding the polypeptide) of the invention and at least one pharmaceutically acceptable carrier, diluent or excipient and/or adjuvant, and optionally one or more further pharmaceutically active polypeptides and/or compounds (Para. 0003, 0010, 0194, 0231, 0397, 0631, 0632, 0741).
Verdonck does not teach that the other nanobodies present in the multi-specific and/or multi-valent polypeptide constructs are anti-TNF-alpha nanobodies having more than 95% identical to SEQ ID NOs: 4 and 6 and fully comprising the CDRs of SEQ ID NOs: 8, 11, and 14.
However, Totsuka teaches that the combination of anti-TNF-alpha and anti-OX40L antibodies is more effective in treating chronic colitis in mice than either antibody alone (see Abstract as well as the paragraph before Discussion on Page G598).
Beirnaert further teaches nanobody constructs that specifically target TNF-alpha and have one or more several advantages over anti-TNF alpha nanobodies known in the prior art, including increased affinity or specificity for TNF-alpha, less immunogenicity, increased stability, and/or better suitability for re-formatting into multivalent or multi-specific formats (see Abstract, Summary of Invention, Claims, and Para. 14 and 15). The nanobody TNF14, in particular, has the amino acid sequence of SEQ ID NO: 77. The amino acid sequence of SEQ ID NO: 77 is more than 95% identical to either SEQ ID NO: 4 or SEQ ID NO: 6 of the instant claims and fully comprises the CDRs of SEQ ID NOs: 8, 11, and 14 of the instant claims (see Table 25).
It would have been obvious to one of ordinary skill in the art to modify the multi-specific polypeptides disclosed by Verdonk such that it comprises two anti-OX40L nanobodies selected from SEQ ID NOs: 202 to 205 as well as two anti-TNF-alpha nanobodies each having the amino acid sequence of SEQ ID NO: 77. One of ordinary skill in the art would have been motivated to do so since 1) the combination of anti-OX40L and anti-TNF-alpha antibodies is more effective in treating an autoimmune disorder in a subject than targeting either antigen alone as taught by Totsuka and 2) the anti-TNF-alpha nanobody disclosed by Beirnaert have increased affinity/specificity for TNF-alpha, less immunogenicity, increased stability and suitability for re-formatting into multivalent and/or multi-specific constructs compared to TNF-alpha nanobodies known in the prior art. Further, artisans would be motivated to provide at least two anti-OX40L nanobodies and at least two anti-TNF-alpha nanobodies in the multi-specific polypeptide in order to increase avidity for each antigen, consistent with Verdonck’s teaching that incorporating two or more nanobodies targeting the same antigen (e.g. OX40L) enhances avidity. Additionally, it would have been obvious for artisans to combine the nanobodies in different ways N-terminal to C-terminal to yield the formats recited in the claims. Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum combination and orientation of the ISVDs present in the polypeptides as well as optimum linker length according to the different embodiments of the instantly claimed invention. Therefore, one of ordinary skill in the art would expect that a multi-specific, multi-valent nanobody construct that specifically targets OX40L and TNF-alpha to be able to effectively treat an autoimmune disorder in a subject.
Claims 9-11 and 28-30 are rejected under 35 U.S.C. 103 as being unpatentable over Verdonck in view of Totsuka and Beirnaert, as applied to claims 2, 26, 33 and 34 above, and further in view of Buyse (CA3005488A1, of record).
While Verdonck teaches that the multi-specific polypeptides can also comprise a nanobody against human serum albumin for increased half-life, Verdonck in combination with Totsuka and Beirnaert does not specifically teach that the nanobody that targets human serum albumin comprises the polypeptide sequence of SEQ ID NO: 5.
However, Buyse teaches nanobody constructs that specifically target serum albumin and are improved variants over anti-serum albumin nanobodies known in the prior art, having reduced interaction with pre-existing antibodies present in the sera of a subject which bind to the C-terminal region of the immunoglobulin single variable domain, thus increasing binding to serum albumin. Further, the anti-serum albumin nanobodies disclosed by Buyse exhibit low frequency and height of T cell responses that could potentially result in the development of a helper T cell immune response (see entire document, in particular, Abstract; Page 3, Ln. 7-8 to Page 4, Ln. 1-3; and Page 4, Ln. 32-34 to Page 5, Ln. 1-8). In particular, Buyse discloses an anti-human serum albumin nanobody having the amino acid sequence of SEQ ID NO: 10, corresponding to SEQ ID NO: 5 recited in the instant claims.
It would have been obvious to one of ordinary skill in the art to modify the multi-specific polypeptide constructs taught by Verdonck in view of Totsuka and Beirnaert such that the anti-human serum albumin nanobody is substituted with that of Buyse having the amino acid sequence of SEQ ID NO: 10, corresponding to SEQ ID NO: 5 of the instant claims. One of ordinary skill in the art would have been motivated to do so since the anti-human serum albumin nanobody disclosed by Buyse exhibits improved binding to serum albumin and low frequency and height of unwanted T cell responses. Therefore, one of ordinary skill in the art would expect that modifying the multi-specific polypeptide taught by Verdonck in view of Totsuka and Beirnaert such that the anti-human serum albumin nanobody is substituted with that of Buyse can improve the half-life of the multi-specific polypeptide without eliciting unwanted T cell responses.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 2, 26, 33 and 34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 8962807B2 in view of Totsuka et al (Totsuka, T et al. American journal of physiology. Gastrointestinal and liver physiology vol. 284,4 (2003): G595-603, of record), hereinafter Totsuka and Beirnaert (US20140335101A1, of record).
The issued patent recites polypeptides that comprise one or more immunoglobulin single variable domains (ISVDs) that specifically bind to OX40L and has the CDRs of SEQ ID NOs: 133, 147, and 161, corresponding to SEQ ID NOs: 7, 10, and 13 of the instant claims, wherein the ISVD is a VH domain, a VHH, or a partially or fully humanized VHH (issued claims 1 and 4). The polypeptides can have the sequence of SEQ ID NOs: 202 to 205 each of which is at least 95% identical to SEQ ID NOs: 2 and 3 of the instant claims and fully comprise the CDRs of SEQ ID NOs: 7, 10, and 13 of the instant claims (issued claim 3). The polypeptide further comprises one or more other residues or binding units, optionally linked via one or more peptide linkers, wherein the binding units are single domain antibodies (issued claims 5 and 6). The polypeptide constructs can be multi-valent and/or multi-specific and can comprise one or more single domain antibodies that bind to human serum albumin to provide the polypeptide with an increased half-life (issued claims 7-9). Compositions comprising the immunoglobulin single variable domains and a carrier are also recited (issued claims 13 and 16).
Thus, while the issued patent recites multi-specific and/or multi-valent polypeptide constructs comprising anti-OX40L nanobodies having the CDRs of SEQ ID NOs: 7, 10, and 13 joined to one or more other nanobodies, the issued patent does not teach that the other nanobodies are anti-TNF-alpha nanobodies of SEQ ID NO: 4 or 6 comprising the CDRs of SEQ ID NOs: 8, 11, and 14.
However, Totsuka teaches that the combination of anti-TNF-alpha and anti-OX40L antibodies is more effective in treating chronic colitis in mice than either antibody alone (see entire document, in particular, Abstract and paragraph before Discussion on Page G598).
Beirnaert further teaches nanobody constructs that specifically target TNF-alpha and having one or more several advantages over anti-TNF alpha nanobodies known in the prior art, including increased affinity or specificity for TNF-alpha, less immunogenicity, increased stability, and/or better suitability for re-formatting into multivalent or multi-specific formats (see entire document, in particular, Abstract, Summary of Invention, Claims, and Para. 14 and 15). The nanobody TNF14, in particular, has the amino acid sequence of SEQ ID NO: 77, which is at least 95% identical to SEQ ID NOs: 4 and 6 of the instant claims and fully comprises the CDRs of SEQ ID NOs: 8, 11, and 14 recited in the instant claims (see entire document, in particular, Table 25).
It would have been obvious to one of ordinary skill in the art to modify the multi-specific polypeptides disclosed by the issued patent such that they further comprise anti-TNF-alpha nanobodies of SEQ ID NO: 77 disclosed by Beirnaert and are at least 95% identical to SEQ ID NOs: 3 and 6 of the instant claims and fully comprise the CDRs of SEQ ID NOs: 8, 11, and 14. One of ordinary skill in the art would have been motivated to do so since 1) the combination of anti-OX40L and anti-TNF-alpha monoclonal antibodies is more effective in treating an autoimmune disorder in a subject than either antibody alone; and 2) anti-TNF-alpha nanobody disclosed by Beirnaert have increased affinity/specificity for TNF-alpha, less immunogenicity, increased stability and suitability for re-formatting into multivalent and/or multi-specific constructs compared to TNF-alpha nanobodies known in the prior art. Additionally, it would have been obvious for artisans to combine the nanobodies in different ways N-terminal to C-terminal to yield the formats recited in the claims. Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum combination and orientation of the ISVDs present in the polypeptides as well as optimum linker length according to the different embodiments of the instantly claimed invention. Therefore, one of ordinary skill in the art would expect that a multi-specific, multi-valent nanobody construct that specifically targets OX40L and TNF-alpha to be able to effectively treat an autoimmune disorder in a subject.
Claims 9-11 and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 8962807B2 in view of Totsuka and Beirnaert, as applied to claims 2, 26, 33 and 34 above, and further in view of Buyse (CA3005488A1, of record).
While the issued claims recite that the polypeptides can also comprise a nanobody against human serum albumin for increased half-life, the issued claims in combination with Totsuka and Beirnaert do not specifically teach that the nanobody that targets human serum albumin comprises the polypeptide sequence of SEQ ID NO: 5.
However, Buyse teaches nanobody constructs that specifically target serum albumin and are improved variants over anti-serum albumin nanobodies known in the prior art, having reduced interaction with pre-existing antibodies present in the sera of a subject which bind to the C-terminal region of the immunoglobulin single variable domain, thus increasing binding to serum albumin. Further, the anti-serum albumin nanobodies disclosed by Buyse exhibit low frequency and height of T cell responses that could potentially result in the development of a helper T cell immune response (see entire document, in particular, Abstract; Page 3, Ln. 7-8 to Page 4, Ln. 1-3; and Page 4, Ln. 32-34 to Page 5, Ln. 1-8). In particular, Buyse discloses an anti-human serum albumin nanobody having the amino acid sequence of SEQ ID NO: 10, corresponding to SEQ ID NO: 5 recited in the instant claims.
It would have been obvious to one of ordinary skill in the art to modify the multi-specific polypeptide constructs taught by issued claims in view of Totsuka and Beirnaert such that the anti-human serum albumin nanobody is substituted with that of Buyse having the amino acid sequence of SEQ ID NO: 10, corresponding to SEQ ID NO: 5 of the instant claims. One of ordinary skill in the art would have been motivated to do so since the anti-human serum albumin nanobody disclosed by Buyse exhibits improved binding to serum albumin and low frequency and height of unwanted T cell responses. Therefore, one of ordinary skill in the art would expect that modifying the multi-specific polypeptide taught by the issued claims in view of Totsuka and Beirnaert such that the anti-human serum albumin nanobody is substituted with that of Buyse can improve the half-life of the multi-specific polypeptide without eliciting unwanted T cell responses.
Claims 2, 26, 33 and 34 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10822425B2 in view of Totsuka et al (Totsuka, T et al. American journal of physiology. Gastrointestinal and liver physiology vol. 284,4 (2003): G595-603, of record), hereinafter Totsuka and Beirnaert (US20140335101A1, of record).
The issued patent recites a polypeptide that comprises one or more immunoglobulin single variable domains that specifically bind to OX40L having the amino acid sequence of SEQ ID NOs: 200-205, 186, 193, 194, 229, or 230, each of which are more than 95% identical to SEQ ID NOs: 2 and 3 of the instant claims and fully comprises the CDRs of SEQ ID NOs: 7, 10, and 13 recited in the instant claims, wherein the immunoglobulin single variable domain is a VH domain, a VHH, or a partially or fully humanized VHH (issued claims 1, 3, 4, and 10). The polypeptide further comprises one or more other residues or binding units, optionally linked via one or more peptide linkers, wherein the binding units are single domain antibodies (issued claims 5 and 6). The polypeptide constructs can be multivalent and/or multi-specific and can comprise one or more single domain antibodies that bind to human serum albumin to provide the polypeptide with an increased half-life (issued claims 7-9). Compositions comprising the immunoglobulin single variable domains and a carrier are also recited (issued claims 13 and 14).
Thus, while the issued patent recites multi-specific and/or multi-valent polypeptide constructs comprising anti-OX40L nanobodies having the CDRs of SEQ ID NOs: 7, 10, and 13 joined to one or more other nanobodies, the issued patent does not teach that the other nanobodies are anti-TNF-alpha nanobodies of SEQ ID NO: 4 or 6 comprising the CDRs of SEQ ID NOs: 8, 11, and 14.
However, Totsuka teaches that the combination of anti-TNF-alpha and anti-OX40L antibodies is more effective in treating chronic colitis in mice than either antibody alone (see entire document, in particular, Abstract and paragraph before Discussion on Page G598).
Beirnaert further teaches nanobody constructs that specifically target TNF-alpha and having one or more several advantages over anti-TNF alpha nanobodies known in the prior art, including increased affinity or specificity for TNF-alpha, less immunogenicity, increased stability, and/or better suitability for re-formatting into multivalent or multi-specific formats (see entire document, in particular, Abstract, Summary of Invention, Claims, and Para. 14 and 15). The nanobody TNF14, in particular, has the amino acid sequence of SEQ ID NO: 77, which is at least 90% identical to SEQ ID NOs: 4 and 6 of the instant claims and fully comprises the CDRs of SEQ ID NOs: 8, 11, and 14 recited in the instant claims (see entire document, in particular, Table 25).
It would have been obvious to one of ordinary skill in the art to modify the multi-specific polypeptides disclosed by the issued patent such that they further comprise anti-TNF-alpha nanobodies of SEQ ID NO: 77 disclosed by Beirnaert. SEQ ID NO: 77 is more than 95% identical to SEQ ID NOs: 3 and 6 of the instant claims and fully comprise the CDRs of SEQ ID NOs: 8, 11, and 14. One of ordinary skill in the art would have been motivated to do so since 1) the combination of anti-OX40L and anti-TNF-alpha monoclonal antibodies is more effective in treating an autoimmune disorder in a subject than either antibody alone and 2) the anti-TNF-alpha nanobody disclosed by Beirnaert have increased affinity/specificity for TNF-alpha, less immunogenicity, increased stability and suitability for re-formatting into multivalent and/or multi-specific constructs compared to TNF-alpha nanobodies known in the prior art. Further, artisans would be motivated to provide at least two anti-OX40L nanobodies and at least two anti-TNF-alpha nanobodies in the multi-specific polypeptide in order to increase avidity for each antigen. Additionally, it would have been obvious for artisans to combine the nanobodies in different ways N-terminal to C-terminal to yield the formats recited in the claims. Lastly, the courts have stated "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); thus, it would have been prima facie obvious to one of ordinary skill in the art to determine by routine experimentation the optimum combination and orientation of the ISVDs present in the polypeptides as well as optimum linker length according to the different embodiments of the instantly claimed invention. Therefore, one of ordinary skill in the art would expect that a multi-specific, multi-valent nanobody construct that specifically targets OX40L and TNF-alpha to be able to more effectively treat an autoimmune disorder in a subject.
Claims 9-11 and 28-30 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 10822425B2 in view of Totsuka and Beirnaert, as applied to claims 2, 26, 33 and 34 above, and further in view of Buyse (CA3005488A1, of record).
While the issued claims recite that the polypeptides can also comprise a nanobody against human serum albumin for increased half-life, the issued claims in combination with Totsuka and Beirnaert do not specifically teach that the nanobody that targets human serum albumin comprises the polypeptide sequence of SEQ ID NO: 5.
However, Buyse teaches nanobody constructs that specifically target serum albumin and are improved variants over anti-serum albumin nanobodies known in the prior art, having reduced interaction with pre-existing antibodies present in the sera of a subject which bind to the C-terminal region of the immunoglobulin single variable domain, thus increasing binding to serum albumin. Further, the anti-serum albumin nanobodies disclosed by Buyse exhibit low frequency and height of T cell responses that could potentially result in the development of a helper T cell immune response (see entire document, in particular, Abstract; Page 3, Ln. 7-8 to Page 4, Ln. 1-3; and Page 4, Ln. 32-34 to Page 5, Ln. 1-8). In particular, Buyse discloses an anti-human serum albumin nanobody having the amino acid sequence of SEQ ID NO: 10, corresponding to SEQ ID NO: 5 recited in the instant claims.
It would have been obvious to one of ordinary skill in the art to modify the multi-specific polypeptide constructs taught by issued claims in view of Totsuka and Beirnaert such that the anti-human serum albumin nanobody is substituted with that of Buyse having the amino acid sequence of SEQ ID NO: 10, corresponding to SEQ ID NO: 5 of the instant claims. One of ordinary skill in the art would have been motivated to do so since the anti-human serum albumin nanobody disclosed by Buyse exhibits improved binding to serum albumin and low frequency and height of unwanted T cell responses. Therefore, one of ordinary skill in the art would expect that modifying the multi-specific polypeptide taught by the issued claims in view of Totsuka and Beirnaert such that the anti-human serum albumin nanobody is substituted with that of Buyse can improve the half-life of the multi-specific polypeptide without eliciting unwanted T cell responses.
Response to Arguments
Applicant's arguments filed 11/24/2025 have been fully considered but they are not persuasive.
With respect to the rejections made under 35 U.S.C. 103, Applicant argues that, as currently amended, the polypeptides recited in claims 2, 26, 33, and 34 have sequences that are very similar to those that were reduced to practice in the Examples and that were found to have unexpected properties. Moreover, the ISVDs of the claimed polypeptides have the same CDR sequences as the ISVDs of the polypeptides that were reduced to practice in the Examples and that were found to have unexpected properties. Applicants assert that these unexpected results could not have been predicted in view of the cited prior art. In addition, Applicants assert that the unexpected results are commensurate in scope with the amended claims. As such, unexpected results support the nonobviousness of the claims.
In response to Applicant's arguments, the Examiner notes the results of the data provided in Example 1 of the Specification cannot be extrapolated to the broad genus polypeptides comprising amino acid sequences having more than 95% identity to SEQ ID NOs: 2, 3, 4, 5, and/or 6 as recited in the instant claims with the expectation that the results will still be applicable to every member that is encompassed by the genus of polypeptides. In fact, it is stated in Example 1 that the exact composition (including valency, linker length, and orientation of ISVD building blocks) of the polypeptide constructs made in Example 1 were critical for different parameters assessed such as potency, cross-reactivity, and expression. In addition, the Examiner notes that the polypeptide constructs consist of ISVD building blocks have fully-defined amino acid sequences as well as a GS linker of varying lengths. For example, the polypeptide construct F027300252 (SEQ ID NO: 1) has the following structure: 1E07/1_BB1 (SEQ ID NO: 2) – 9GS linker – 1E07/1_BB2 (SEQ ID NO: 3) – 9GS linker – 1C02/1_BB3 (SEQ ID NO: 4)– 9GS linker – ALB23002 (SEQ ID NO: 5) – 9GS linker –1C02/1_BB5 (SEQ ID NO: 6) (see Tables A-1 on Page 51 and Table A-3 on Page 54). While F027300252 reportedly has improved potency, superior expression levels, and Chemistry, Manufacturing and Control (CMC) characteristics, these alleged unexpected results may not be seen across the entire genus of polypeptide constructs recited in the claims which can have different linkers of varying compositions and lengths as well as undefined amino acid mutations in the framework regions of the ISVD building blocks: similarity alone is insufficient to establish that the claimed fusion proteins would necessarily possess the same functional properties as those exemplified. In other words, Applicant’s assertion of unexpected results is not commensurate in scope with the claimed genus, which encompasses polypeptides comprising amino acid sequences with at least 90% identity to SEQ ID NOs: 2, 3, 4, and/or 6 (and thus undefined amino acid mutations) as well as different linkers of varying compositions and lengths. The specification does not demonstrate that the alleged unexpected results is attributable to the genus as a whole but rather to specific polypeptide species comprising an exact composition, including valency, type of linker, linker length, as well as the orientation and amino acid sequences of the ISVD building blocks. Therefore, Applicant’s arguments fail to rebut the prima facie case of obviousness discussed in the rejection above.
Conclusion
Claims 4, 5, 8, 12, 13, 17, 27, 31, and 32 are allowable. Claims 2, 9, 10, 11, 26, 28, 29, 30, 33, and 34 are not allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641
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