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 Group I (i.e., claims 50-60 drawn to a method for preventing or reducing the binding by pre-existing antibodies to a heavy-chain immunoglobulin single variable domain or a polypeptide) in the reply filed on January 16, 2024, is acknowledged. Moreover, Applicant’s election of Species A (i.e., a single and specific heavy-chain immunoglobulin single variable domain with a N-glycosylation site at position 108) in the reply filed on January 16, 2024, is acknowledged. 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)).
Please note that in light of the search results, Species B is expanded to position 14.
Status of Claims
Claims 1-37 were originally filed on March 17, 2022.
The amendment received on June 28, 2022, canceled claims 1-37; and added new claims 38-63. The amendment received on July 24, 2024, amended claims 50 and 60. The amendment received on February 14, 2025, canceled claim 63; amended claim 60; and added new claim 64. The amendment received on October 2, 2025, amended claims 38-40 and 50-52.
Claims 38-62 and 64 are currently pending and claims 50-60 and 64 are under consideration as claims 38-49 and 61-62 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on January 16, 2024.
Priority
The present application is a continuation of US Application No. 15/554,744, filed on August 31, 2017, which claims status as a 371 (National Stage) of PCT/EP2016/055947 filed March 18, 2016, and claims priority under 119(e) to U.S. Provisional Application No. 62/135,968 filed on March 20, 2015.
Response to Arguments
Applicant’s arguments, see Response, filed 10/2/25, with respect to the 103(a) rejection have been fully considered and are persuasive. The rejection of claims 50-52, 59-60, and 64 as being unpatentable over Ashman et al. WO 2013/024059 A2 published on February 21, 2013, in view of Filpula et al. US Patent No. 6,323,322 B1 issued on November 27, 2001, and de Marco, A., Microbiol. Cell Factories 10:14 pages (2011) has been withdrawn.
Maintained/Modified Rejections in light of Applicants’ Amendments
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.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 50-60 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over Ashman et al. WO 2013/024059 A2 published on February 21, 2013, in view of Hultberg et al. US Publication No. 2011/0182897 A1 published on July 28, 2011 (cited in the IDS received on 06/28/22), Kolkman et al., WIPO Publication No. 2008/020079 A1 published on February 21, 2008 (cited in the IDS received on 06/28/22), and de Marco, A., Microbiol. Cell Factories 10:14 pages (2011), alone or as evidenced by UniProt, Glycosylation, available online at https://www.uniprot.org/help/carbohyd, 4 pages (first available 2014 and last updated 2018) (cited in the IDS received on 06/28/22). Please note that the rejection has been updated in light of Applicants’ amendments.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
For claims 50-60, with respect to a method for reducing the binding by pre-existing antibodies to a heavy-chain immunoglobulin single variable domain (HC-ISVD) or a polypeptide comprising the same, where the HC-ISVD consists of formula I: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 by introducing at least one glycosylation site into the part of the nucleotide sequence that encodes the HC-ISVD such that the amino acid residue at position 108 can be glycosylated where the numbering is according to Kabat numbering as recited in instant claim 50; with respect to where an N-glycosylation site is introduced such that the amino acid residue at position 108 is an asparagine residue that can be N-glycosylated as recited in instant claims 51, 54, and 57; where an N-glycosylation site is introduced such that the HC-ISVD contains an NXT or NXS motif, in which X can be any amino acid, such that the asparagine residue of the NXT/NXS motif is present at position 108 as recited in instant claims 52, 55, and 58; with respect to where the glycosylation site is introduced such that the amino acid residue at position 108 can be glycosylated as recited in instant claims 53 and 56; with respect to where the HC-ISVD is or is derived from a VHH, a humanized VHH, a human VH or camelized human VH as recited in instant claim 59; and with respect to a method for reducing the binding by pre-existing antibodies to a polypeptide where the HC-ISVD is at the C-terminal end of the polypeptide as recited in instant claim 60:
Ashman et al. teaches modified proteins and peptides that have reduced ability to bind to pre-existing antibodies where the modified protein/peptide (i.e., thereby constituting the instantly claimed polypeptide as recited in instant claims 50 and 60) can comprise C-terminal additions, extensions or tags and/or certain amino acid substitutions (See Ashman specification, pg. 1, 1st paragraph; pg. 3, 2nd paragraph). Such modified protein/peptide molecules including fusions thereof can comprise antigen binding molecules such as single variable domains, e.g., human HC-ISVDs and those derived from non-human sources such as llama or camel, e.g., VHH including a Nanobody™ (See Ashman specification, pg. 1, 1st paragraph; pg. 3, 2nd paragraph; pg. 5, 6th paragraph) thereby constituting the HC-ISVD as recited in instant claim 50, a polypeptide comprising the HC-ISVD as recited in instant claim 50, where the HC-ISVD is or is derived from VHH or humanized VHH as recited in instant claim 59, and where the HC-ISVD is at the C-terminal end of the polypeptide as recited in instant claim 60. Pre-existing anti-VH autoantibodies (ADAs) are present in sera from subjects that bind both VH domain antibodies and VHH molecules where the reactivity between the ADAs and the VH domain antibodies and VHH molecules appears specific to a neo epitope, or epitopes, within the VH domain antibody (dAb) framework sequence since the response was cross-reactive with the VH frameworks of dAbs binding various target antigens but not with full human IgG (See Ashman specification, pg. 2, 7th paragraph). Ashman et al. determined that modifications which alter the three dimensional conformation of the dAb C-terminus in VH and VHH dAbs are important (See Ashman specification, pg. 2, last paragraph to pg. 3, 1st paragraph). In particular, Ashman et al. found that substituting the amino acid residues present at one or more positions of 14, 41, 108, 110 and 112-113 in VH dAbs would result in altered three dimensional conformation of the dAb C-terminus (See Ashman specification, pg. 3, 1st paragraph). Figure 3 shows a model crystal structure highlighting the residues that impact ADA binding when mutated where position 14 had a strong impact on ADA binding when mutated, and residues 41, 108, 110, and 112 had a moderate impact on ADA binding when mutated (See Ashman specification, pg. 11, 2nd paragraph; Figure .3).
Regarding the dAb and substitutions within the dAb, Ashman et al. teaches that the dAb monovalently binds to a target antigen and comprises (a) three CDR regions specific for the target antigen, (b) four framework (FR) regions, (c) a C-terminal sequence consisting of the sequence VTVS(S)nX or VEIKpRqX, and optionally (d) one or more amino acid substitutions at positions 14, 41, 108, 110 or 112 compared to a human germline framework sequence where n is 0 or 1, p and q each represent 0 or 1 such that when p represents 1, q may be 0 or 1, and when p represents 0, q also represents 0; and X may or may not be present, and if present represents 1 to 8 amino acid residues (See Ashman specification, pg. 4, 3rd paragraph). Furthermore, Ashman et al. teaches that the one or more substitutions can be selected from a P14A, P14K, P14Q, P14T, P41A, L108A, L108Q, T110A, and S112A substitution (See Ashman specification, pg. 5, 5th paragraph; pg. 19, 2nd-3rd paragraph). As such, the L108Q substitution would result in the motif: QVT. It is noted that although Ashman’s dAb contains a C-terminal extension amino acid sequence (i.e., component (c)), which is not encompassed by the instantly claimed dAb in light of the transitional phrase “consists of”, since the instantly claimed FR4 is not limited in a specific amino acid sequence or length, the C-terminal extension amino acid sequence is encompassed by the instantly claimed FR4 region. As such, the dAb taught by Ashman et al. constitutes the HC-ISVD consisting of formula 1: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 as recited in instant claim 50. Moreover, Ashman et al. teaches nucleic acids encoding the dAbs of the invention (See Ashman specification, pg. 8, last paragraph). Furthermore, Ashman et al. teaches that the dAbs of the invention can contain post-translational modifications such as the addition of various sugar moieties in various glycosylation patterns (See Ashman specification, pg. 24, last paragraph). Ashman et al. also teaches that the invention includes glycosylation variants of the antigen binding proteins where one or more carbohydrate moiety is added, substituted, deleted or modified (See Ashman specification, pg. 24, last paragraph). Introduction of an N-X-S or N-X-T motif creates a potential site for enzymatic attachment of carbohydrate moieties and may therefore be used to manipulate the glycosylation of an antibody (See Ashman specification, pg. 24, last paragraph). As such, the teachings of Ashman et al. encompass introducing an N-X-S or N-X-T motif to create a glycosylation site. Thus, Ashman et al. teaches that binding to pre-existing antibodies (i.e., ADAs) can be reduced by substituting the amino acid residues present at one or more positions of 14, 41, 108, 110 and 112-113 in VH dAbs whereby such substitution alters the three dimensional conformation of the dAb C-terminus, and teaches that the dAbs can contain an introduced N-X-S or N-X-T motif to create a glycosylation site thereby constituting a method for reducing the binding by pre-existing antibodies to a HC-ISVD or polypeptide comprising the same by introducing a modification into the part of the nucleic acid sequence that encodes the HC-ISVD such that the amino acid residue at position 108 is substituted and introducing an N-X-S or N-X-T motif to create a glycosylation site as recited in instant claim 50.
However, Ashman et al. does not teach that the substitution at the amino acid at position 108 in VH dAbs results in a glycosylation site, a N-glycosylation site, or an NXT or NXS motif as recited in instant claims 50-58.
Hultberg et al. teaches Nanobodies® that are directed against an envelope protein of a virus (See Hultberg specification, [0228]). Generally, Nanobodies can be characterized by the presence of one or more “Hallmark residues” in one or more of the framework sequences (See Hultberg specification, [0230]). Moreover, Hultberg et al. teaches that a Nanobody® can be defined as an amino acid sequence with the general structure: FR1–CDR1–FR2–CDR2–FR3–CDR3–FR4 in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively (See Hultberg specification, [0231]-[0234], [0351], [0614]–[0615], [0846], [1115]-[1120], [1125]-[1136], [1151]-[1181], [1202]-[1212]). Furthermore, Hultberg et al. teaches that the Nanobody or polypeptide is glycosylated or non-glycosylated (See Hultberg specification, [1437]). Hultberg et al. also teaches that it is preferred that one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104, and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table B-2 (See Hultberg specification, Table B-2) where the amino acid residue at position 108 are Gln, Leu, or Arg (See Hultberg specification, Table B-2). When the amino acid residue at position 108 is Gln, it forms the motif: QVT (i.e., amino acid residues corresponding to positions 108-110). Hultberg et al. also teaches that in the Nanobodies, any amino acid substitution (when it is not a humanizing substitution) can be a conservative substitution (See Hultberg specification, [0281], [0362], [1267]). Moreover, Hultberg et al. teaches that the skilled person may take into account “conservative” amino acid substitutions as described on page 50 of WO 08/020079 (See Hultberg specification, [0775]). Similarly, Hultberg et al. teaches that a substitution may for example be a conservative substitution and/or an amino acid residue may be replaced by another amino acid residue that naturally occurs at the same position in another VHH domain as described in Tables B-4 to B-7 (See Hultberg specification, [1280]). Thus, the teachings of Hultberg et al. suggest that the amino acid residues at positions 108-110 in SEQ ID NOs: 1-2, 4-7, 9-13, and 15-22 are QVT and where the residues can be conservatively substituted, and suggest where the Nanobody can be glycosylated, and when combined with the teachings of Ashman et al., an ordinary skilled artisan would understand that the QVT motif at positions 108-110 include a Hallmark residue that can be conservatively substituted, and which Ashman et al. found to reduce binding by pre-existing antibodies by altering the three dimensional conformation of the dAb C-terminus.
De Marco teaches that N-glycosylation on VHHs aids in improving their neutralizing capacity against viruses in vitro and in vivo and increasing their mass thereby allowing the binding site on each toxin molecule to be blocked (See de Marco article, pg. 4, col. 2, 1st paragraph; pg. 5, col. 2, 1st paragraph). Moreover, de Marco teaches that N-glycosylation allows the antibody stability tuning and can improve the antibody effectiveness in vivo (See de Marco article, pg. 4, col. 2, 1st paragraph; pg. 5, col. 2, 1st paragraph). Therefore, de Marco suggests advantages of N-glycosylation on VHHs including improved efficacy and increased stability.
Kolkman et al. teaches that preferred the conservative substitution for Gln is Asn where such a preferred substitution is between polar, negatively charged residues and their uncharged amides (See Kolkman specification, pg. 50, last two paragraphs). Thus, the teachings of Kolkman et al. suggest that Gln and Asn are preferred conservative substitutions exhibiting similar physical and chemical properties. As evidenced by the UniProt reference, the consensus sequence for N-glycosylation is Asn-Xaa-Ser/Thr (where Xaa is not Pro) (See UniProt reference, pg. 2, 3rd paragraph). As such, as evidenced by the UniProt reference, the conservatively substituted asparagine residue corresponding to the amino acid residues at position 108 in Hultberg’s SEQ ID NOs: 1-2, 4-7, 9-13, and 15-22 can be N-glycosylated.
Therefore, an ordinary skilled artisan would be motivated with a reasonable expectation of success to substitute the amino acid residues at position 108-110 of Ashman et al. with QVT as suggested by Hultberg et al. where the Gln residue is conservatively substituted to Asn as suggested by Kolkman thereby forming the amino acid motif at positions 108-110 of NVT where such substitutions will alter the HC-ISVD 3D conformation, improve efficacy, and increase stability of the HC-ISVD thereby resulting in reduced binding to pre-existing antibodies.
For claim 64, with respect to where the method further comprises expressing, in a glycosylated form, the HC-ISVD or the polypeptide comprising the same, and measuring binding by pre-existing antibodies to the glycosylated form:
Regarding expressing the HC-ISVD, as discussed supra, Ashman et al. teaches nucleic acids encoding the dAbs of the invention and vectors and host cells comprising these nucleic acids (See Ashman specification, pg. 8, last paragraph; pg. 9, 5th paragraph). Ashman et al. also teaches methods of producing the dAbs of the invention comprising expressing the encoding vectors and nucleic acids in host cells (See Ashman specification, pg. 9, 5th paragraph; pg. 18, 1st to 3rd paragraph). The encoded peptide or polypeptide is produced via expression under suitable conditions in a host cell or in an in vitro expression system (See Ashman specification, pg. 18, 2nd-3rd, 5th paragraph). Thus, the teachings of Ashman et al. satisfy the claim limitation with respect to expressing a modified dAb containing a substitution at one or more positions 14, 41, 108, 110 or 112 compared to a human germline framework sequence as recited in instant claim 64.
Regarding measuring binding by pre-existing antibodies to the glycosylated form, Ashman et al. teaches that the modified dAbs have reduced ADA binding where such reduced binding to ADAs is determined using a confirmation assay as described in Example 2 where the modified dAb has a mean % inhibition of signal which is less than 90% in comparison with a control dAb which has around 98%-100% (See Ashman specification, pg. 16, 2nd paragraph; pg. 40, last paragraph to pg. 42, 1st paragraph and Table 1). In order to determine the reduced binding of the modified dAbs to ADAs by using a confirmation assay, it would necessarily follow that the binding by pre-existing ADAs to the modified dAbs is measured. Thus, the teachings of Ashman et al. satisfy the claim limitation with respect to measuring binding by pre-existing antibodies to a modified dAb containing a substitution at one or more positions 14, 41, 108, 110 or 112 compared to a human germline framework sequence as recited in instant claim 64.
Regarding the HC-ISVD being in glycosylated form for expression and measurement, as discussed supra, Ashman et al. teaches expressing a modified dAb where the modified dAb contains a substitution at one or more positions 14, 41, 108, 110 or 112 compared to a human germline framework sequence such as QVT for positions 108-110 where such substitution alters the 3D conformation of the dAb and where the modified dAb can contain a chemical modification such as the introduction of an N-X-S or N-X-T motif to create a glycosylation site, and teaches measuring binding by ADAs to the modified dAbs.
Moreover, as discussed supra for claim 50, Hultberg et al. suggest that the amino acid residues at positions 108-110 in SEQ ID NOs: 1-2, 4-7, 9-13, and 15-22 are QVT and where the residues can be conservatively substituted, and suggest where the Nanobody can be glycosylated. Hultberg et al. also teaches that the compounds or polypeptides (thereby including the Nanobodies) can generally be prepared by providing a nucleic acid that encodes the polypeptide, expressing the nucleic acid in a suitable manner, and recovering the expressed polypeptide (See Hultberg specification, paragraph [0627], [0679]-[0680]). Plus, Hultberg et al. teaches hosts or host cells that express (or that under suitable circumstances are capable of expressing) an amino acid sequence of the invention and/or a polypeptide of the invention; and/or contains a nucleic acid of the invention (See Hultberg specification, paragraph [0634]). As such, Hultberg et al. suggests expressing a Nanobody that contains the motif, QVT, at positions 108-110 in SEQ ID NOs: 1-2, 4-7, 9-13, and 15-22 and where these residues can be conservatively substituted, and suggests where the Nanobody can be glycosylated.
Therefore, an ordinary skilled artisan would be motivated with a reasonable expectation of success to express a modified dAb by substituting the amino acid residues at position 108-110 of Ashman et al. with QVT as suggested by Hultberg et al. where the Gln residue is conservatively substituted to Asn as suggested by Kolkman thereby forming the amino acid motif at positions 108-110 of NVT, glycosylating the Asn residue given the finite number of states, i.e., glycosylated or non-glycosylated state, and then measure the binding by pre-existing antibodies to the suggested modified dAb in glycosylated form where such substitutions will alter the HC-ISVD 3D conformation thereby resulting in reduced binding to pre-existing antibodies, improve efficacy, and increase stability of the HC-ISVD.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.012)
Ashman et al. does not expressly teach a method for reducing the binding by pre-existing antibodies to a HC-ISVD or a polypeptide comprising the same wherein the HC-ISVD consists of formula 1: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 by introducing into the part of the nucleotide sequence that encodes the HC-ISVD such that the amino acid residues at positions 108-110 are NVT where the Asn residue that can be glycosylated as recited in instant claims 50-58. However, the teachings of Hultberg et al., Kolkman et al., and de Marco cure this deficiency by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
Ashman et al. does not expressly teach expressing, in a glycosylated form, the HC-ISVD or the polypeptide comprising the same and measuring binding by pre-existing antibodies to the glycosylated form as recited in instant claim 64. However, the teachings of Hultberg et al., Kolkman et al., and de Marco cure this deficiency by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or utilizing an "Obvious to try" rationale - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success pursuant to KSR.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-4143)
With respect to a method for reducing the binding by pre-existing antibodies to a HC-ISVD or a polypeptide comprising the same wherein the HC-ISVD consists of formula 1: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 by introducing into the part of the nucleotide sequence that encodes the HC-ISVD such that the amino acid residues at positions 108-110 are NVT where the Asn residue that can be glycosylated as recited in instant claims 50-58, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant application to modify the teachings of Ashman et al. and introduce at least one glycosylation site into the part of the nucleotide sequence that encodes a HC-ISVD consisting of formula 1: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 such that the amino acid residues at positions 108-110 are substituted with QVT and the Gln residue is conservatively substituted to Asn thereby altering the HC-ISVD’s 3D conformation, improving efficacy, and increasing stability of the HC-ISVD in order to reduce the binding by pre-existing antibodies to a HC-ISVD or a polypeptide comprising the same. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because nanobodies were known to contain a QVT motif at positions 108-110 where the residues can be conservatively substituted and where the nanobodies can be glycosylated as taught by Hultberg et al.; because a Gln to Asn substitution was known to constitute a conservative substitution as taught by Kolkman et al.; and because N-glycosylation on VHHs was known to improve efficacy and increase stability of the VHH as taught by de Marco. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the HC-ISVD of Ashman et al. consisted of formula 1: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 such that the amino acid residue at position 108 was substituted in order to alter the HC-ISVD’s 3D conformation thereby resulting in the reduction of binding by pre-existing antibodies to the HC-ISVD. Therefore, substituting the amino acid residues at positions 108-110 with the motif QVT where the Gln is conservatively substituted to Asn thereby forming the NXT motif would support the reduction of binding by pre-existing antibodies to the HC-ISVD by altering the HC-ISVD’s 3D conformation, improving efficacy, and increasing stability of the HC-ISVD by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention pursuant to KSR.
With respect to expressing, in a glycosylated form, the HC-ISVD or the polypeptide comprising the same and measuring binding by pre-existing antibodies to the glycosylated form as recited in instant claim 64, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the instant application to modify the teachings of Ashman et al. and express a nucleotide sequence that encodes a modified HC-ISVD consisting of formula 1: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 where the modification results in a glycosylated HC-ISVD by introducing a QXT motif at positions 108-110 and the Gln residue is conservatively substituted to Asn resulting in a NXT glycosylation motif in a host, and measuring the binding by pre-existing antibodies to the modified glycosylated HC-ISVD where such measurement indicates reduced binding by pre-existing antibodies to the modified glycosylated HC-ISVD or a polypeptide comprising the same. One of ordinary skill in the art at the time the invention was made would have been motivated to do so because nanobodies were known to contain a QVT motif at positions 108-110 where these residues can be conservatively substituted, where the nanobodies were known to be glycosylated, and the nanobodies were known to be expressed in a host or host cell as taught by Hultberg et al.; because a Gln to Asn substitution was known to constitute a conservative substitution as taught by Kolkman et al.; and because N-glycosylation on VHHs was known to improve efficacy and increase stability of the VHH as taught by de Marco. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the modified HC-ISVD containing a substitution at position 108 and an added glycosylation site by introducing a NXT motif of Ashman et al. is expressed in a host, and reduces binding to pre-existing antibodies where such reduction in binding is measured via a confirmation assay. Therefore, expressing the modified HC-ISVD where the modification results in a NXT motif being is introduced at positions 108-110 in a host would support the modified HC-ISVD being in a glycosylated form given the finite number of structural states, i.e., glycosylated or non-glycosylated, and would support the reduction of binding by pre-existing antibodies to the HC-ISVD by altering the HC-ISVD’s 3D conformation, improving efficacy, and increasing stability of the HC-ISVD by constituting some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention and/or utilizing an "Obvious to try" rationale - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success pursuant to KSR.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Applicants’ Arguments
Applicants contend that the claimed invention is nonobvious because (1) the Examiner has failed to justify (i.e., motivate) why an ordinary skilled artisan would have specifically selected one of the claimed positions for the introduction of the glycosylation site as the cited references fail to teach introducing a glycosylation site specifically at one of the claimed positions to improve efficacy and increase stability of a VHH; in other words, why would an ordinary skilled artisan start with the amino acid motif of QVT at positions 108-110, especially given that Ashman teaches away from utilizing T at position 110 (See Applicant’s Response received on 10/2/25, pg. 8-9); (2) even if an ordinary skilled artisan would have started with the amino acid motif of QVT at positions 108-110, the Examiner has failed to establish why an ordinary skilled artisan would have introduced a conservative substitution for Q108 since Hultberg repeatedly identified Q and L resulting from humanization of Q108 as preferred, especially given that Hultberg teaches that substitutions, insertions or deletions at the Hallmark residues are generally less preferred unless these are suitable humanizing substitutions where N is not identified as a suitable humanizing substitution for position 108 (See Applicant’s Response received on 10/2/25, pg. 10); (3) the Examiner has failed to establish why an ordinary skilled artisan would have selected N as a conservative substitution for Q at position 108 since Kolkman provides various conservative substitutions for Q including D, N, and E (See Applicant’s Response received on 10/2/25, pg. 10); (4) an ordinary skilled artisan would not have had a reasonable expectation of success in achieving reduced binding by pre-existing antibodies using the claimed method because the combined cited references do not teach or suggest that introducing a glycosylation site at one of the claimed positions could be used to reduce binding of pre-existing antibodies to a HC-ISVD in view of the teachings of Ashman that any change to the 3D-conformation of an ISVD (or any substitution at positions 14, 41, 108, 110, and 112) can be used to reduce binding of pre-existing antibodies, let alone that introducing a glycosylation site at one of the claimed positions could be used for this purpose (See Applicant’s Response received on 10/2/25, pg. 10-11).
Response to Arguments
Applicant's arguments filed 10/2/25 for claims 50-60 and 64 have been fully considered but they are not persuasive for the following reasons.
As stated in the Action mailed on 7/2/25, the Examiner would like to point out the interpretation of claim 50. It is noted that claim 50 only requires one manipulative step; namely, introducing at least one glycosylation site such that the glycosylation site is located at one of the claimed positions of a HC-ISVD consisting of formula I (hereinafter referred to as “modified HC-ISVD”). It is further noted the method requires reduced binding by pre-existing antibodies to the modified HC-ISVD in the preamble. All that is recited is the step of introducing at least one glycosylation site AND reduced binding by pre-existing antibodies to the modified HC-ISVD. As such, the Examiner maintains that one interpretation of the claim scope encompasses modifying a HC-ISVD by introducing at least one glycosylation site such that the glycosylation site is located at one of the claimed positions of a HC-ISVD consisting of formula I (note: thereby meeting the manipulative step limitation and structural limitation of the wherein clause), and the resulting modified HC-ISVD structure would necessarily exhibit the function of reduced binding to pre-existing antibodies or would necessarily result in reduced binding to pre-existing antibodies.
In response to Applicant’s first argument, i.e., the Examiner has failed to justify (i.e., motivate) why an ordinary skilled artisan would have specifically selected one of the claimed positions for the introduction of the glycosylation site as the cited references fail to teach introducing a glycosylation site specifically at one of the claimed positions to improve efficacy and increase stability of a VHH; in other words, why would an ordinary skilled artisan start with the amino acid motif of QVT at positions 108-110, especially given that Ashman teaches away from utilizing T at position 110, it is found unpersuasive. As stated in the Action mailed on 11/14/24, it is acknowledged that there is not a single reference that teaches and/or suggests every claim limitation recited in instant claims 50 and 60 and the dependent claims. However, Applicants are respectfully reminded that the rejection supra is based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Additionally, the Examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). Furthermore, pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984).
In the instant case, as discussed in the 103 rejection supra, Ashman expressly teaches modifying fusion proteins and peptide comprising an HC-IVSD where such modified fusions have reduced ability to bind to pre-existing antibodies. Ashman expressly teaches modifying fusion proteins and peptide comprising an HC-IVSD where such modified fusions have reduced ability to bind to pre-existing antibodies. Ashman expressly suggests that the modification of the fusion protein resulting in the fusion having reduced ability to bind to pre-existing antibodies is due to an altered 3D-conformation of the C-terminus such that the amino acid residue present at one or more positions of 14, 41, 108, 110 and 112-113 are substituted. Importantly, Ashman depicts in Figure 3 a model crystal structure highlighting the residues that impact ADA binding when mutated where position 108 had a moderate impact on ADA binding when mutated (See Ashman, pg. 11, 2nd paragraph). Plus, Ashman expressly demonstrates in Example 2 that when using the confirmation assay three specific substitutions; namely, P14A, P41A, and L108Q, resulted in significantly reduced pre-existing ADA binding while retaining potency for TNFR1 (See Ashman, pg. 41, last paragraph to pg. 42, 1st paragraph). As such, Ashman teaches the tripeptide motif at positions 108-110 of QVT that exhibits reduced pre-existing ADA binding while retaining potency for TNFR1. Although Ashman teaches that position T110 can be substituted, Ashman expressly teaches that the L108Q substitution exhibits reduced pre-existing ADA binding while retaining potency for TNFR1 when the residue at position 110 is T. It is noted that Ashman does not require that both positions 108 and 110 must be substituted to achieve the intended result. Moreover, Ashman expressly suggests that a new glycosylation site can be introduced into the HC-ISVD, albeit, does not expressly suggest that the added glycosylation site is located at one of the positions having a substituted residue. Thus, an ordinary skilled artisan would have the requisite motivation to start with the tripeptide motif: QVT at positions 108-110. The question is then whether an ordinary skilled artisan would be motivated to substitute N108 for Q108 thereby resulting in a N-glycosylation site of NVT with a reasonable expectation of success. The Examiner maintains that the answer to this question is yes in light of the teachings of Hultberg, de Marco and Kolkman. Hultberg et al. suggests Nanobodies containing mutations including at “Hallmark” residues such as at position 108 where the mutation can be L108Q thereby resulting in the tripeptide motif: QVT at positions 108-110. Hultberg et al. also teaches that a glycosylation site can be removed or added (See Hultberg, [1281]). Furthermore, Hultberg et al. teaches that conservative substitutions are encompassed including any one or more substitutions, deletions or insertions, that either improve the properties of the Nanobody or that at least do not detract too much from the desired properties or from the balance or combination of desired properties of the Nanobody (See Hultberg, [1280]). For example, Hultberg teaches modifications that introduce one or more functional groups that increase the half-life, the solubility and/or the absorption of the Nanobody, that reduce the immunogenicity and/or the toxicity of the Nanobody, that eliminate or attenuate any undesirable side effects of the Nanobody, and/or confer other advantageous properties to and/or reduce the undesired properties of the Nanobody where the modification can be N-linked or O-linked glycosylation (See Hultberg, [1307], [1311]). Although Hultberg considers a N-linked glycosylation modification to be less preferred, a less preferred modification does not constitute a teaching away. Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). As such, as discussed in the rejection supra, when the teachings of Hultberg are combined with the teachings of Ashman et al., an ordinary skilled artisan would understand that the QVT motif at positions 108-110 include a Hallmark residue that can be conservatively substituted, and which Ashman et al. found to reduce binding by pre-existing antibodies by altering the three dimensional conformation of the dAb C-terminus. de Marco expressly suggests how it is advantageous to introduce a N-glycosylation site in VHHs by improving efficacy and increasing stability. Kolkman provides the motivation to substitute N for Q where this substitution is between polar, negatively charged residues and their uncharged amides. Therefore, when the cited references are combined, the Examiner maintains that an ordinary skilled artisan would be motivated with a reasonable expectation of success to start with the tripeptide motif of QVT at positions 108-110 of a HC-ISVD, and further modify this tripeptide motif to NVT where such modification will alter the HC-ISVD 3D conformation, improve efficacy, and increase stability of the HC-ISVD thereby resulting in reduced binding to pre-existing antibodies.
In response to Applicant’s second argument, i.e., even if an ordinary skilled artisan would have started with the amino acid motif of QVT at positions 108-110, the Examiner has failed to establish why an ordinary skilled artisan would have introduced a conservative substitution for Q108 since Hultberg repeatedly identified Q and L resulting from humanization of Q108 as preferred, especially given that Hultberg teaches that substitutions, insertions or deletions at the Hallmark residues are generally less preferred unless these are suitable humanizing substitutions where N is not identified as a suitable humanizing substitution for position 108, it is found unpersuasive. Pursuant to MPEP 2141, “[a] prior art reference must be considered in its entirety, i.e., as a whole, including portions that would lead away from the claimed invention. W.L. Gore & Assoc., Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), cert. denied, 469 U.S. 851 (1984). Pursuant to MPEP 2123 (II), “[d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Although it is acknowledged that Hultberg at [1279] teaches that when substitutions, insertions or deletions at the Hallmark residues are generally less preferred unless these are suitable humanizing substitutions, such teaching does not constitute a teaching away but rather a non-preferred embodiment. As discussed in the rejection supra, Hultberg expressly refers to Kolkman with respect to conservative substitutions. As such, it is clear that Hultberg envisions conservative substitutions including at the Hallmark residues. Thus, contrary to Applicant’s argument, when considering the teachings of Hultberg as a whole, in combination with the other cited references, the Examiner maintains that an ordinary skilled artisan would understand Hultberg as encompassing conservative substitutions even at the Hallmark residues; especially, when the modification results in an improved property such as improved half-life in light of the teachings of de Marco (note: improved half-life is a species of improved stability).
In response to Applicant’s third argument, i.e., the Examiner has failed to establish why an ordinary skilled artisan would have selected N as a conservative substitution for Q at position 108 since Kolkman provides various conservative substitutions for Q including D, N, and E, it is found unpersuasive. It is acknowledged that Kolkman identifies D, N and E as conservative substitutions for Q (See Kolkman, pg. 50, 4th paragraph). However, three possible substitutions constitutes a finite number of identified, predictable solutions (note: given similar properties shared among the four residues). As such, at a minimum, an ordinary skilled artisan would be motivated to try to substitute N for Q utilizing an obvious-to-try rationale (See MPEP 2143(I)(E)). Furthermore, it is noted that such a small group of alternatives would even fall under the In re Petering rationale if the rejection was one of anticipation. Thus, although Kolkman suggests that D and E also can be conservatively substituted for Q, an ordinary skilled artisan would have the requisite motivation to select N as a conservative substitution for Q given the shared similar properties.
In response to Applicant’s fourth argument, i.e., an ordinary skilled artisan would not have had a reasonable expectation of success in achieving reduced binding by pre-existing antibodies using the claimed method because the combined cited references do not teach or suggest that introducing a glycosylation site at one of the claimed positions could be used to reduce binding of pre-existing antibodies to a HC-ISVD in view of the teachings of Ashman that any change to the 3D-conformation of an ISVD (or any substitution at positions 14, 41, 108, 110, and 112) can be used to reduce binding of pre-existing antibodies, let alone that introducing a glycosylation site at one of the claimed positions could be used for this purpose, it is found unpersuasive. As stated in the Action mailed on 7/2/25, pursuant to MPEP 2143.02(II), obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). As an initial matter, Applicant asserts that Ashman “makes clear that not all substitutions at the indicated positions would be expected to reduce binding of pre-existing antibodies”, but fails to provide a citation to support the assertion. Although Ashman teaches that the % of reduced binding can vary, e.g., 10% less binding up to 90% less binding (see Ashman discussion for claim 64 in the rejection supra), and that mutations at position 108 had a moderate impact on ADA binding (See Ashman, pg. 11, 2nd paragraph), Ashman expressly demonstrates in Example 2 that when using the confirmation assay three specific substitutions; namely, P14A, P41A, and L108Q, resulted in significantly reduced pre-existing ADA binding while retaining potency for TNFR1 (See Ashman, pg. 41, last paragraph to pg. 42, 1st paragraph). Pursuant to MPEP 2152.02(b), in order for a prior art document to describe a claimed invention under AIA 35 U.S.C. 102(a)(1) or (a)(2), the prior art document need only describe and enable one skilled in the art to make a single species or embodiment of the claimed invention. See Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1562, 19 USPQ2d 1111, 1115 (Fed. Cir. 1991). As such, it is unnecessary for Ashman to demonstrate all substitutions at position 108 that would result in reduced binding to pre-existing antibodies. Given that Ashman found that the L108Q mutation resulted in reduced binding to pre-existing antibodies while retaining potency for TNFR1, given that Hultberg teaches that position 108 is a Hallmark residue including where the residue at position 108 can be Q, which can be conservatively substituted, and given that Kolkman teaches that Q can be conservatively substituted with N in light of the similar properties shared between Q and N, the Examiner maintains that an ordinary skilled artisan would have the requisite expectation of success that the added glycosylation site at position 108 would similarly alter the 3D conformation of the HC-ISVD in order to reduce binding between pre-existing antibodies and the modified HC-ISVD. Furthermore, it is noted that the scope of claim 50 only requires the glycosylation site to be introduced at position 108 and not that the HC-ISVD is glycosylated. Thus, although glycosylation is distinct from one or more substitutions, since claim 50 does not require the HC-ISVD to be glycosylated, the introduction of a glycosylation site (i.e., substitution L108Q and Q108N) constitutes substitutions at these positions.
Additionally, it is noted that there is no required manipulative step of reduced binding by pre-existing antibodies to the modified HC-ISVD. There is only one required manipulative step of introducing a glycosylation site (note: no requirement that the HC-ISVD is glycosylated), which correlates to a manipulative step of modifying the HC-ISVD structure. Moreover, there is no correlation between the manipulative step of introducing a glycosylation site and the intended use of reduced binding by pre-existing antibodies recited in the preamble. As such, contrary to Applicant’s argument, since the only required manipulative step in claim 50 is directed to modifying the HC-ISVD structure, as long as the claimed manipulative step is met, the claimed intended use of the modified HC-ISVD would necessarily be met; especially since Ashman et al. expressly correlates an altered 3D conformation when the HC-ISVD contains a substitution at position 108 with reduced binding to pre-existing antibodies.
It is further noted that Applicants have not provided evidence to support their argument that an ordinary skilled artisan would not reasonably expect a conformational alteration by introducing a glycosylation site at position 108 of a HC-ISVD. This argument is merely the argument of counsel and is unsupported by evidence or declarations of those skilled in the art. Attorney argument is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See M.P.E.P. § 2129 and § 2144.03 for a discussion of admissions as prior art. Counsel's arguments cannot take the place of objective evidence. In re Schulze, 145 USPQ 716 (CCPA 1965); In re Cole, 140 USPQ 230 (CCPA 1964); and especially In re Langer, 183 USPQ 288 (CCPA 1974). See M.P.E.P. § 716.01(c) for examples of attorney statements that are not evidence and that must be supported by an appropriate affidavit or declaration.
Accordingly, the rejection of claims 50-60 and 64 is maintained as Applicants’ arguments are found unpersuasive.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 50-60 and 64 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 11,306,139 B2 (Buyse et al.) (cited in the IDS received on 6/28/22). Although the claims at issue are not identical, they are not patentably distinct from each other because Buyse et al. claims:
PNG
media_image1.png
232
647
media_image1.png
Greyscale
PNG
media_image2.png
116
653
media_image2.png
Greyscale
PNG
media_image3.png
125
634
media_image3.png
Greyscale
PNG
media_image4.png
143
631
media_image4.png
Greyscale
PNG
media_image5.png
87
626
media_image5.png
Greyscale
PNG
media_image6.png
74
639
media_image6.png
Greyscale
PNG
media_image7.png
227
633
media_image7.png
Greyscale
PNG
media_image8.png
205
634
media_image8.png
Greyscale
PNG
media_image9.png
195
628
media_image9.png
Greyscale
PNG
media_image10.png
119
625
media_image10.png
Greyscale
PNG
media_image11.png
95
626
media_image11.png
Greyscale
PNG
media_image12.png
205
629
media_image12.png
Greyscale
(See ‘139 claims 1-3, 17, 19, 21, and 38-42 thereby corresponding to issued claims 1-3, 11-13, 17, 21-24). Thus, the ‘139 claimed HC-ISVD encompasses the instantly claimed HC-ISVD. However, ‘139 does not claim that the HC-ISVD reduces the binding by pre-existing antibodies.
Regarding the instantly claimed use and where the method further comprises expressing, in glycosylated form, the HC-ISVD and measuring binding by pre-existing antibodies to the glycosylated form, pursuant to MPEP 804, In AbbVie Inc. v. Kennedy Institute of Rheumatology Trust, 764 F.3d 1366, 112 USPQ2d 1001 (Fed. Cir. 2014), the court explained that it is also proper to look at the disclosed utility in the reference disclosure to determine the overall question of obviousness in a nonstatutory double patenting context. See Sun Pharm. Indus., Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 95 USPQ2d 1797 (Fed. Cir. 2010); Pfizer, Inc. v. Teva Pharm. USA, Inc., 518 F.3d 1353, 86 USPQ2d 1001 (Fed. Cir. 2008); Geneva Pharmaceuticals Inc. v. GlaxoSmithKline PLC, 349 F3d 1373, 1385-86, 68 USPQ2d 1865, 1875 (Fed. Cir. 2003). Thus, even though the instant claims recite specificities not explicitly recited by the claims of the reference application, disclosed utilities of the instant claims encompassed by the claims of the reference application are disclosed in the specification of the reference application, and thus the instant claims are not patentably distinct from the claims of the reference application. In the instant case, ‘139 teaches that the present invention aims to provide a technique for reducing the binding of pre-existing antibodies to ISVDs by suitably introducing at least one glycosylation site into the same such that in the resulting Ig (single) variable domain, polypeptide, protein, compound, construct or other chemical entity, the at least one glycosylation site is glycosylated (See ‘139 specification, col. 3, 4th paragraph; col. 6, last paragraph to col. 7, 3rd paragraph) thereby constituting where the ‘139 claimed HC-ISVDs are used in a method of reducing the binding by pre-existing antibodies to HC-ISVDs by introducing at least one glycosylation site as recited in instant claim 50. ‘139 also teaches introducing one or more codons that encode a glycosylation site into a nucleotide sequence that encodes an Ig (single) variable domain, where the nucleotide can then be expressed in a suitable host cell or host organism to provide the Ig (single) variable domain om glycosylated form (See ‘139 specification, col. 3, 2nd to 3rd paragraph) thereby constituting expressing, in a glycosylated form, the HC-ISVD or the polypeptide comprising the same as recited in instant claim 64. Moreover, ‘139 teaches that a reduction of binding by pre-existing antibodies is calculated by the method described in Example 3 based on binding data obtained for a set of relevant serum samples, which binding data is measured for each sample and comparing it to a suitable reference (See ‘139 specification, col. 17, 3rd paragraph; col. 29-30, Example 3) thereby constituting measuring binding by pre-existing antibodies to the glycosylated form as recited in instant claim 64. Therefore, the ‘139 claimed invention is not patentably indistinct from the instantly claimed invention.
Applicants’ Arguments
Applicants state that Applicant will consider filing a terminal disclaimer once the claims are otherwise in condition for allowance (See Applicants Response received on 10/2/25, pg. 11).
Response to Arguments
Applicant’s statement that filing a terminal disclaimer once the claims are otherwise in condition for allowance will be considered is acknowledged. As such, the double-patenting rejection is maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to THEA D' AMBROSIO whose telephone number is (571)270-1216. The examiner can normally be reached on M-F 11:00 to 8:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/THEA D' AMBROSIO/Examiner, Art Unit 1654