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 .
Election/Restrictions
Applicant’s election of the invention of Group I, drawn to an immunoglobulin single variable domain (ISVD) capable of binding to serum albumin, in the reply filed on 11/11/25 is acknowledged. Applicant further elects an anti-serum albumin ISVD species in which (i) the amino acid residue at Kabat position 5 is V, (ii) the amino acid residue at Kabat position 11 is V; (iii) the amino acid residue at Kabat position 16 is N; (iv) the amino acid residue at Kabat position 45 is L; (v) the amino acid residues at Kabat positions 74 to 76 is AKT; (vi) the amino acid residue at Kabat position 89 is L; and (vii) the amino acid residue at Kabat position 104 is T, and wherein the ISVD comprises a C-terminal alanine extension. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 41, 43, 45, 48, 49, 51, 52, 53, and 54 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 11/11/25.
Claims 35-38, 40, 42, 44, 46, 47, and 50 are examined on the merits in the present Office Action.
Claim Interpretation
As discussed further in the rejection under 35 USC 112(b), claim 35 simultaneously requires the presence of amino acid residues not present in SEQ ID NO: 1 (i.e. the CDR of SEQ ID NO: 120 as well as the recited framework residues at Kabat positions 5, 11, 16, 45, 74 to 76, 89, and 104) and limits the total number of amino acid differences relative to SEQ ID NO: 1 to be seven or less not taking into account the CDRs, framework residues/substitutions, and any C-terminal extension. These claim limitations are mutually exclusive and cannot both be satisfied. For the purposes of examination, claim 35 is interpreted as broadly encompassing an immunoglobulin single variable domain (ISVD) comprising the amino acid sequence of SEQ ID NO: 1 modified such that (i) the CDR1 corresponds to SEQ ID NO: 120 (SEQ ID NOs: 6 and 7 are already present in SEQ ID NO: 1); (ii) the framework residues at positions 5, 11, 16, 45, 74 to 76, 89, and 104 are substituted as recited in the claim, and (iii) up to seven additional amino acid substitutions can be present in the framework regions.
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, 40, 42, 44, 46, 47, and 50 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 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.
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 – including the elected species –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 and do not appear to represent the structural diversity of the genus of ISVD variants recited in the claims—let alone the elected species—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, 40, 42, 44, 46, 47, and 50 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 – including the elected species –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 – including the elected species –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.
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 35-38, 40, 42, 44, 46, 47, and 50 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.
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.
First, it is unclear if the exclusion of “the amino acid sequences of the CDRs, the amino acids at Kabat positions 5, 11, 16, 45, 74 to 76, 89, and 104, and any C-terminal extension” refers to those as present in SEQ ID NO: 1 or to the CDRs and specific framework residues recited earlier in the claim.
Second – regardless of which amino acid residues/CDRs are excluded – as presently written, the amino acid sequence of claim 1 appear to comprise the CDRs of the serum albumin VHH clone Alb-8 (SEQ ID NO: 50) (see Table A on Page 4 of the specification) while using the amino acid sequence of clone Alb-23 (SEQ ID NO: 1) as the reference sequence for determining the number of amino acid differences. The claim further requires that the amino acid sequence differ from SEQ ID NO: 1 by no more than 7 amino acids with the exclusion of the CDRs, amino acid residues at Kabat positions 5, 11, 16, 45, 74 to 76, 89, and 104, and any C-terminal extension from the determination of the number of amino acid differences. However, SEQ ID NO: 1 does not contain the recited CDR sequences -specifically CDR1 – or the recited framework residues/substitutions; and incorporation of these required features necessarily introduces more than seven amino acid differences relative to SEQ ID NO: 1. Thus, the claim simultaneously requires the presence of amino acid residues not present in SEQ ID NO: 1 and limits the total number of amino acid differences relative to SEQ ID NO: 1 to be seven or less not taking into account the CDRs, framework residues/substitutions, and any C-terminal extension. These claim limitations are mutually exclusive and cannot both be satisfied. For example, an amino acid sequence having the CDRs and the recited framework residues/substitutions does not satisfy the limitation on the number of amino acid differences permitted in SEQ ID NO: 1. Alternatively, an amino acid sequence that has no more than 7 amino acid sequences relative to SEQ ID NO: 7 not taking into account the recited CDRs, framework residues/substitutions at Kabat positions 5, 11, 16, 45, 74 to 76, and 104, and any C-terminal extension would not satisfy the structural limitations recited earlier in the claim. Therefore, claim 35 does not clearly set forth the metes and bounds of the patent prosecution desired. Claims 36-38, 40, 42, 44, 46, 47, and 50 depend directly or indirectly from claim 1 but do not cure the deficiencies of claim 1 and are thus also rejected.
Claim 38 recites a protein, polypeptide or other construct, compound, molecule, or chemical entity according to claim 37 (which comprises the anti-serum albumin ISVD), comprises at least one therapeutic moiety or entity.
As presently written, it is unclear if the anti-serum ISVD of claim 35 represents the therapeutic moiety or entity or if the structures recited in claim 38 comprise one or more therapeutic moieties in addition to the anti-serum ISVD. Therefore, claim 38 does not clearly set forth the metes and bounds of the patent prosecution desired.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 35-38, 40, 42, 44, 46, 47, and 50 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Buyse et al (US20170121399A1), hereinafter Buyse.
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
Buyse discloses immunoglobulin single variable domain (ISVD) that bind to human serum albumin, wherein the ISVD is a nanobody or VHH having a C-terminal alanine extension and one or more specific amino acid residues/substitutions (according to Kabat numbering) in order to reduce the binding of pre-existing antibodies/factors (Abstract, Para. 0005, 0022-0026, 0031, and 0034-0036) In a particular embodiment, the nanobody or VHH is Alb-8 (SEQ ID NO: 46) with a C-terminal extension (X)n in which n = 1 to 5 and X is, for example, alanine; leucine (L) at Kabat position 89; and valine (V) at position 11 (Para. 0161, 0163-0164, 0166). Further, the amino acid residue at Kabat position 104 in the in the FW4 region can be, for example, threonine (T). The unmodified amino acid sequence of Alb-8 comprises the CDRs of SEQ ID NOs: 120, 6, and 7 recited in the instant claims; lacks a C-terminal extension; and contains the following, according to Kabat numbering: valine (V) at position 5, leucine (L) at position 11, asparagine (N) at position 16, L at position 45, the amino acid motif AKT at positions 74 to 76, V at position 89, and serine (S) at position 104. After incorporation of the substitutions described above, Alb-8 can include a C-terminal alanine extension and the following, according to Kabat numbering;
the amino acid residue at position 5 is V (present in unmodified sequence);
the amino acid residue at position 11 is V (modified);
the amino acid residue at position16 is N (present in unmodified sequence);
the amino acid residue at position 45 is L (present in unmodified sequence);
the amino acid motif at positions 74 to 76 is AKT (present in unmodified sequence);
the amino acid residue at position 89 is L (modified);
the amino acid residue at position 104 is T (modified).
In this modified form, clone Alb-8 has the amino acid sequence identical to that of the elected species and encompassed by the instant claims. Lastly, the ISVDs/nanobodies can further comprise one or more therapeutic moieties (Para. 0089).
Thus, Buyse meets the limitations of instant claims 35-38, 40, 42, 44, 46, 47, and 50.
Conclusion
No claims are allowable.
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/LIA E TAYLOR/Examiner, Art Unit 1641
/MICHAEL SZPERKA/Primary Examiner, Art Unit 1641