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 Amendment
Applicant’s remarks and amendments to the claims received 05/11/2026 have been acknowledged. Claims 35 and 38 have been amended. The claim amendments overcome rejections made under 35 USC 112(b). The prior art exception under 35 USC 102(b)(2)(C) raised by Applicant overcomes the rejection under 35 USC 102(a)(2).
Election/Restrictions
The elected species was found free of the prior art in view of the prior art exception under 35 USC 102(b)(2)(C) raised by Applicant. Thus, the species election has been withdrawn. Claims 41, 43, 45, 48, 49, 51, and 52 previously withdrawn are hereby rejoined and examined on the merits in the present Office Action.
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 35-38 and 40-52 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.
The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or 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 genus (MPEP 2163).
In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
“A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”
The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC 2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
Claim 35 recites an amino acid sequence that is an immunoglobulin single variable domain (ISVD) capable of binding to serum albumin and comprising the CDRs of SEQ ID NOs: 120, 6, and 7 as well as the recited amino acid residues/substitutions in the framework regions at Kabat positions 5, 11, 16, 45, 74 to 76, 89, and 104, wherein the amino acid sequence has no more than 7 additional amino acid differences with the amino acid sequence of SEQ ID NO: 1 and the CDRs; amino acids at Kabat positions 5, 11, 16, 45, 74 to 76, 89, and 104; and any C-terminal extensions are not taken into account in determining the number of amino acid differences.
Unlike conventional antibodies, in which the framework regions (FRs) primarily serve as a structural scaffold to support the complementarity-determining regions (CDRs), it is well-recognized in the art that framework residues in single domain antibodies (VHHs or nanobodies) directly contribute to antigen binding and expand the surface area of the paratope (see, e.g. Zavrtanik et al: Abstract, Results on pp. 4372-4373, 5th para. of Discussion on pp 4380, and Highlights; Mitchell et al: 3rd para of Introduction, Figure 1, and 1st para. of Discussion; and Ketaran et al, 1st para. of Discussion). In particular, residues within FR2, including the characteristic VHH “hallmark residues” at IMGT positions 42, 49, 50, and 52, as well as residues within FR3, have been shown to influence binding affinity and stability. In fact, certain FR2 substitutions such as Phe42Val and Gly/Ala52Trp have been reported to be detrimental for antigen affinity due to a repositioning of the CDR3 (H3) loop (Vincke et al, Abstract and last paragraph on Page 3273 that spans to page 3274). Similarly, mutations intended to enhance stability can adversely affect binding: for example, a single FR3 point mutation G78A introduced to increase thermal stability resulted in an order-of-magnitude decrease in binding affinity due to a shift in the conformational space of the paratope (Ikeuchi et al, see Abstract and Page 3). Other substitutions within FR3 can also disrupt the stabilizing interactions and lead to reduced antigen binding such as mutation of the highly conserved residue Phe69 (Ketaren et al, Abstract, 2nd para. on Page 6, and 1st para. of Discussion).
Given the number of combinations possible with the recited framework residue/substitutions and the fact that mutations in the FRs of nanobodies/VHH can potentially reduce binding affinity, the claimed genus appears to encompass ISVD variants that were neither made nor tested for binding to serum albumin; and the specification provides no evidence that the structure of each ISVD variant encompassed by claim 35 having the recited framework residues/substitutions as well as up to 7 random amino acid mutations in the FRs is correlated with the functional property of binding to serum albumin. The ISVD variants disclosed in Tables C, D, E, F, G, and H of the specification are based on the reference sequence of SEQ ID NO: 119 (“reference A”) and do not appear to represent the structural diversity of the genus of ISVD variants recited in the claims correlated with the functional property of binding to serum albumin (Pages 95 to 101). Without further testing, artisans would not be able to readily identify the ISVD variants encompassed by claim 35 having the recited CDRs, framework residues/substitutions, and up to 7 random amin acid mutations that possess the functional property of biding to serum albumin commensurate in scope of the claim.
Therefore, the claimed genus of amino acid sequences comprising an ISVD capable of binding to serum albumin lacks adequate written description because there does not appear to be any correlation between the structure of the claimed ISVDs – including the elected species – having the recited CDRs, framework residues/substitutions, and up to 7 undefined amino acid mutations, and the function of binding to serum albumin. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of anti-serum albumin ISVDs at the time the instant application was filed.
Enablement
Claims 35-38 and 40-52 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 35 recites an amino acid sequence that is an immunoglobulin single variable domain (ISVD) capable of binding to serum albumin and comprising the CDRs of SEQ ID NOs: 120, 6, and 7 as well as the recited amino acid residues/substitutions in the framework regions at Kabat positions 5, 11, 16, 45, 74 to 76, 89, and 104, wherein the amino acid sequence has no more than 7 amino acid differences with the amino acid sequence of SEQ ID NO: 1 and the CDRs; amino acids at Kabat positions 5, 11, 16, 45, 74 to 76, 89, and 104; and any C-terminal extensions are not taken into account in determining the number of amino acid differences. The elected ISVD species has the following amino acid residues/substitutions: 5V, 11V, 16N, 45L, AKT motif at positions 74 to 76, 89L, and 104T. There is no evidence provided in the specification that each ISVD variant encompassed by claim 35 having the recited framework residues/substitutions as well as up to 7 random amino acid mutations in the FRs retains the functional property of binding to serum albumin.
As discussed earlier, the framework residues nanobodies/VHHs directly contribute to antigen binding and expand the surface area of the paratope (see, e.g. Zavrtanik et al: Abstract, Results on pp. 4372-4373, 5th para. of Discussion on pp 4380, and Highlights; Mitchell et al: 3rd para of Introduction, Figure 1, and 1st para. of Discussion; and Ketaran et al, 1st para. of Discussion). In particular, residues within FR2, including the characteristic VHH “hallmark residues” at IMGT positions 42, 49, 50, and 52, as well as residues within FR3, have been shown to influence binding affinity and stability. In fact, certain FR2 substitutions such as Phe42Val and Gly/Ala52Trp, have been reported to be detrimental for antigen affinity due to a repositioning of the CDR3 (H3) loop (Vincke et al, Abstract and last paragraph on Page 3273 that spans to page 3274). Similarly, mutations intended to enhance stability can adversely affect binding: for example, a single FR3 point mutation G78A introduced to increase thermal stability resulted in an order-of-magnitude decrease in binding affinity due to a shift in the conformational space of the paratope (Ikeuchi et al, see Abstract and Page 3). Other substitutions within FR3 can also disrupt the stabilizing interactions and lead to reduced antigen binding such as mutation of the highly conserved residue Phe69 (Ketaren et al, Abstract, 2nd para. on Page 6, and 1st para. of Discussion). Thus, amino acid substitutions/mutations in the FRs of nanobodies or VHH can potentially have a negative impact on antigen binding.
Given the combination of amino acid residues/substitutions possible in the framework regions and the fact that mutations in the FRs of nanobodies/VHH can potentially reduce binding affinity, the claimed genus appears to encompass ISVD variants that were neither made nor tested for binding to serum albumin; and the specification provides no evidence that each ISVD variant encompassed by claim 35 having the recited framework residues/substitutions as well as up to 7 random amino acid mutations in the FRs retains the functional property of binding to serum albumin commensurate in scope of the claim.
Therefore, the specification is not enabling over the full scope of the claims.
Response to Arguments
Applicant's arguments filed 05/11/2026 with respect to the 35 USC 112(a) rejections have been fully considered but they are not persuasive.
With respect to the 35 USC 112(a) rejections, Applicant argues that the claims do not require that the claimed ISVD bind to serum albumin with any particular binding affinity-they merely require that the claimed ISVD be capable of binding serum albumin. Applicant contends that artisans would understand -in view of the specification and prior art -that an ISVD having the claimed combination of CDRs would be capable of binding serum albumin.
In response to Applicant’s arguments, the Examiner notes that the issue is not merely that certain framework substitutions may alter binding affinity but that the claimed ISVDs encompass numerous framework mutations; yet, the evidence of record does not establish that the recited CDR sequences alone are sufficient to preserve serum albumin binding in the presence of the framework mutations encompassed by the claims especially given the fact that framework residues also contribute to antigen binding in VHH antibodies. Vincke, for example, demonstrates that framework residues contribute to the antigen-binding properties of VHHs and that alterations of certain framework residues -specifically hallmark residues –can be detrimental to antigen binding. As such, a skilled artisan would not reasonably conclude that all ISVDs having the recited CDRs and any combination of specified Kabat substitutions as well as up to seven additional framework mutations would retain binding to serum albumin absence of evidence to the contrary. The claims encompass numerous ISVD variants but the specification does not identify which substitutions preserves or abolishes binding. Neither does the specification demonstrate that the CDRs alone are sufficient to maintain antigen binding in the presence of the claimed framework mutations given that fact framework residues can influence binding.
Moreover, in addition to the lack of experimental evidence demonstrating antigen binding across the claimed genus, it is also unclear whether many members of the claimed genus were even generated or otherwise disclosed by Applicant. Thus, applicant has not established that they were in possession of the full scope of the claimed genus at the time of filing. The Examiner notes that the presently claimed ISVD genus encompasses at least 48 distinct variants based solely on the recited combinations of the specified framework mutations at Kabat positions 5, 11, 16, 45, 74-76, 89, and 104. In addition, each of these 48 variants may further include up to seven additional amino acid differences relative to SEQ ID NO: 1, excluding the CDRs, specified Kabat positions, and any C-terminal extension, thereby substantially increasing the number of ISVD sequences encompassed by the claims.
After review of the specification, the Examiner has not been able to identify disclosure of each of the 48 variants defined by the framework residue combinations at the Kabat positions specified. If applicant contends that all of the 48 variants are indeed disclosed, Applicant is requested to identify by sequence identifier where each such variant is disclosed. The written description requirement is not satisfied merely because certain species within a claimed genus are disclosed. The specification must reasonably convey that the inventors were in possession of the full breadth of the claimed genus of anti-serum albumin ISVD variants. Here, the claims encompass numerous ISVD variants differing in framework residues, yet the specification does not appear to disclose representative species commensurate in scope of the claimed genus, in particular, the 48 variants defined the by recited Kabat substitutions.
Thus, the 35 USC 112(a) rejections are maintained.
Conclusion
No claims are allowable.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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