DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendments, filed on 08/28/2025 are acknowledged.
3. Applicant’s election without traverse of claims 28, 30-31, 33-34, 36-38 and 180-191 (Group II) and further election of a single species of polypeptide comprising the base antibody light chain sequence SEQ ID NO: 1; the amino acid sequence substitution of DLRTGT (SEQ ID NO: 17) and the isotype recognition modification sequence YAYVHE (SEQ ID NO: 9), in the reply filed on 08/28/2025 is acknowledged.
4. Claims 1-27, 29, 32, 35, 39-179 are canceled.
Claims 180-191 are new.
Claims 28, 30-31, 33-34, 36-38 and 180-191 are pending.
Claims 33, 36-37 are withdrawn from consideration under 37 CFR 1.142(b) as being drawn to nonelected species. Note claim 33 recites non-elected light chain sequence SEQ ID NOs: 16-23 and claims 36-37 recite non-elected substitutions/deletions.
Claims 28, 30-31, 34, 38 and 180-191 are currently under consideration.
5. Applicant' s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a 371 of PCT/US2020/070664 filed 10/14/2020, which claims benefit of US provisional application 62/914,851 filed 10/14/2019. Claims 28, 30-31, 33-34, 38 and 180-191 have an effective filing date of 10/14/2019.
Claim Rejections - 35 USC § 112
6. 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.
7. Claims 28, 31, 180 and 183-189 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 31 recites the polypeptide of claim 28, wherein the polypeptide comprises at least 70% sequence identity to SEQ ID NO: 2. However, the polypeptide recited in base claim 28 comprises a Fab comprising heavy and light chains, wherein the light chain comprises a constant region set forth as a mutated SEQ ID NO: 1. However, SEQ ID NO: 2 is only 31 residues in length, making it is impossible for the polypeptide of claim 28 to comprise 70% sequence identity to SEQ ID NO: 2 because the peptide of claim 28 is larger than 31 amino acid residues. Based on the specification, it appears that SEQ ID NO: 2 is drawn to the modified protein G Fab binding domain (e.g., specification ¶0304); if this is the case, examiner recommends amending claim 31 to further limit the “protein G Fab binding domain” that is recited in base claim 28.
Claim 28 recites a light chain region comprising a constant region comprising a
substitution/deletion of amino acids corresponding to positions 16-20 of SEQ ID NO: 1 of the
constant region with the amino acids LRT. Dependent claim 180 recites “the antibody light chain comprises a kappa antibody light chain”. According to the specification SEQ ID NO: 1 is the sequence for a kappa light chain, but claim 28 further requires specific amino acid substitutions. These claims are indefinite because the examiner cannot determine whether the kappa light chain recited in claim 180 is merely referencing the light chain set forth in SEQ ID NO: 1, or if claim 180 is claiming an additional light chain.
Claims 188-190 all recite the limitation "the heavy and light chain regions" in line 1 of each claim. There is insufficient antecedent basis for this limitation in these claims. Claims 188-190 all depend upon claim 34, which does not recite heavy and light chains.
Claims 183 and 189 recite a limitation claiming that the heavy and light chain regions of the Fab are conjugated to the protein G Fab binding domain through a linker. These claims are indefinite because the examiner cannot determine whether the applicant intends to claim that either the heavy chain or the light chain of the Fab is being conjugated, or if both of the heavy and light chains are conjugated to the G fab binding domain via two separate linkers or a bi-furcated linker.
8. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
9. Claim 30 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 30 recites the polypeptide of independent claim 28, wherein the constant region comprises the amino acid sequence of DLRTGT (SEQ ID NO: 17) in substitution for the amino acids corresponding to positions 15-22 of SEQ ID NO: 1. However, independent claim 28 recites a constant region comprising a substitution/ deletion of amino acids corresponding to positions 16-20 of SEQ ID NO: 1. Both of these limitations conferring a “substitution/deletion” to SEQ ID NO: 1 result in the same peptide sequence (see alignment below; Qy represents sequence recited in base claim 28 and Db represents sequence recited in dependent claim 30).
Query Match 100.0%; Score 544; DB 1; Length 105;
Best Local Similarity 100.0%;
Matches 105; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RTVAAPSVFIFPPSDLRTGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 RTVAAPSVFIFPPSDLRTGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSK 60
Qy 61 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 105
|||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 105
Therefore, claim 30 fails to specify a further limitation to the claimed subject matter. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
10. 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.
11. Claims 28, 30-31, 34, 38 and 180-191 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming.
Base claim 28 recites, “A polypeptide comprising a Fab… wherein the Fab is conjugated to a protein G Fab binding domain comprising a modified isotype recognition region, wherein the isotype recognition region is modified to YAYVHE (SEQ ID NO: 9)”. Base claim 34 recites, “A polypeptide comprising a Fab conjugated to a protein G Fab binding domain comprising a modified isotype recognition region, wherein the isotype recognition region is modified to YAYVHE (SEQ ID NO:9) Examiner notes that YAYVHE is the elected species of modified isotype recognition region.
Therefore, base claims 28 and 34 recite a genus of polypeptides comprising a Fab that is conjugated to a protein G Fab binding domain with a modified isotype recognition region set forth as YAYVHE (SEQ ID NO: 9). Claims 30-31 and 180-185 are dependent from Claim 28 and claims 38 and 186-191 are dependent from claim 34; these claims do not materially limit the genus of agents, and are therefore included in the rejection. These claims do not require that the genus of the claims possess any particular structure or other distinguishing feature that is characteristic of the genus as a whole. Therefore the claims are drawn to a genus of “polypeptides” for which there is inadequate written description.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), 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 claimed genus MPEP 2163(II)(3)(a)(i)(C).
Regarding the genus of the claims the specification does not describe a single specific within the genus claimed. The broadest reasonable interpretation of the claim limitation “conjugated” is that the Fab and the protein G Fab binding domain are connected to one another, usually via a peptide linker or chemical bond. However, protein G Fab binding domains and protein A Fab binding domains are well known in the art to form high affinity bonds with the constant region of immunoglobulin heavy chains and Fc regions. In consulting the specification examiner notes that the disclosure appears to describe an embodiment where, “… the heavy and light chains of the Fab are conjugated to the protein G Fab binding domain through a linker” (¶0035). However, the specification also describes contradictory descriptions; for instance, the specification discloses that the protein G binding domain binds to the epitope on the Fab, forming a high affinity complex (e.g., ¶0365; see also Figure 1). The specification further describes examples and experimental data for the development and design of a “FabLRT – GA1 complex” (e.g., ¶0372). It appears that the specification as a whole is drawn to FabLRT binding to an affinity matured GA1 protein.
The specification does describe a single construct where a GA1 domain was fused to a heavy chain C-terminus of a Herceptin Fab scaffold (e.g., ¶0384); here again, the GA1 domain appears to be binding to the FabLRT, and is not conjugated (e.g., Fig 9). In fact, the specification does not appear to contain any structural information, such as amino acid sequences or schematic diagrams that outline the design of these constructs which would be expected to contain sequences for amino acid linkers, linker lengths and the location of the conjugation (i.e., N-terminus or C-terminus).
Accordingly, in the absence of sufficient recitation of any distinguishing structure, identifying characteristics, design considerations, or a representative number of species, the specification does not provide adequate written description of the claimed genus.
Claim Rejections - 35 USC § 102
12. 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)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 34, 36-38 and 186-191 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by KOSSIAKOFF et al (WO 2016061427 A1; published 04/21/2016).
Base claim 34 recites, “A polypeptide comprising a Fab conjugated to a protein G Fab binding domain comprising a modified isotype recognition region, wherein the isotype recognition region is modified to YAYVHE (SEQ ID NO:9), YAFGNG (SEQ ID NO:10), or IDMVSS (SEQ ID NO:11)”. Claim 38 further limits the isotype recognition region to the elected species of YAYVHE (SEQ ID NO: 9).
Regarding claims 34 and 38, KOSSIAKOFF teaches methods and compositions of protein F Fab-binding regions (title and abstract). Specifically, KOSSIAKOFF teaches polypeptides comprising modified protein G Fab-binding regions which are engineered to have improved affinity over the wild-type for the Fab region (¶0005). In a specific embodiments, the protein G variant comprises a modified isotype recognition region set forth as YAYVHE (e.g., see construct named “A1”, reported in figure 4A; see also ¶s 0153, 0167). KOSSIAKOFF teaches these modified protein G variants fused to a heavy chain Fab via a flexible linker (e.g., ¶0228, lines 8-11; see figure 14). Therefore, KOSSIAKOFF teaches polypeptides comprising a Fab conjugated to a protein G Fab binding domain comprising a modified isotype recognition region, modified to YAYVHE; as such, KOSSIAKOFF anticipates instant claims 34 and 38.
Regarding claim 186, KOSSIAKOFF teaches the polypeptide of claim 34; KOSSIAKOFF also teaches specific embodiments wherein the Fab light chain is engineered to eliminate binding to the protein G variant (see figures 13 and 16; ¶s 0227-0228). Therefore, KOSSIAKOFF anticipates claim 186.
Regarding claims 187 and 188, KOSSIAKOFF teaches the polypeptide of claim 34, wherein the protein G Fab binding domain has 100% sequence identity to SEQ ID NO: 3 (see alignment below; Qy is SEQ ID NO: 3 and Db is KOSSIAKOFF sequence reported in ¶0144).
Query Match 100.0%; Score 147; DB 1; Length 29;
Best Local Similarity 100.0%;
Matches 29; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RTLSGYTTTTAVDAATAEKVFKQYAYVHE 29
|||||||||||||||||||||||||||||
Db 1 RTLSGYTTTTAVDAATAEKVFKQYAYVHE 29
Regarding claims 188-191, KOSSIAKOFF teaches the polypeptide of claim 34. KOSSIAKOFF also teaches that the Fab domains may be fused through a linker (e.g., see claim 25, pg. 72). Alternatively, KOSSIAKOFF teaches they may be linked via binding affinity (e.g., knob-in-hole) rather than a linker (¶0228). KOSSIAKOFF teaches the Fab and G Fab binding domains are conjugated via a linker (¶0228). KOSSIAKOFF also teaches that the polypeptides further contain antigen binding fragments (e.g., see figures 14 and 16, ¶0228). Therefore, KOSSIAKOFF anticipates claims 188-189 and 191.
Double Patenting
13. 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.
14. Claims 34, 36-38 and 186-191 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-12 of U.S. Patent No. 10759834 B2 (reference) in view of KOSSIAKOFF et al (WO 2016061427 A1; published 04/21/2016).
Regarding instant claims 34 and 38, reference claims 9 and 10 recite a polypeptide comprising a modified protein G fab binding domain comprising at least 90% sequence identity with SEQ ID NO: 3 wherein the variant isotype recognition region consists of SEQ ID NO:20. As detailed below, reference SEQ ID NO: 20 (Db) is the same isotype recognition region of the elected species recited in instant base claim 34 (YAYVHE set forth as SEQ ID NO: 9) (Qy).
RESULT 1
AASEQ2_12302025_025517
Query Match 100.0%; Score 35; DB 1; Length 6;
Best Local Similarity 100.0%;
Matches 6; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 YAYVHE 6
||||||
Db 1 YAYVHE 6
Regarding claim 187, reference claims 9 and 10 depend from reference claims 1 and 8 respectively. These claims further recite a modified protein G fab binding domain comprising an amino acid sequence having at least 90% sequence identity with SEQ ID NO: 3. As detailed below, reference SEQ ID NO: 3 (Db) and SEQ ID NO: 3 of instant claim 187 (Qy) are identical.
Query Match 100.0%; Score 147; DB 1; Length 29;
Best Local Similarity 100.0%;
Matches 29; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 RTLSGYTTTTAVDAATAEKVFKQYAYVHE 29
|||||||||||||||||||||||||||||
Db 1 RTLSGYTTTTAVDAATAEKVFKQYAYVHE 29
The reference claims 1 and 8-10 differ from instant claims 34, 38 and 187 by not reciting that the polypeptide comprises a Fab conjugated to the G Fab binding domain.
KOSSIAKOFF is the preceding WIPO application related to US Pat. No. 10759834 B2 and teaches these modified protein G variants fused to a heavy chain Fab via a flexible linker (e.g., ¶0228, lines 8-11; see figure 14). Therefore, KOSSIAKOFF teaches polypeptides comprising a Fab conjugated to a protein G Fab binding domain comprising a modified isotype recognition region, modified to YAYVHE.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the polypeptide recited in the reference claims to be fused to a heavy chain Fab via a flexible linker (e.g., ¶0228, lines 8-11; see figure 14) as taught by KOSSIAKOFF to achieve the predictable result of obtaining multimeric, antigen-targeting Fab polypeptides. One of ordinary skill in the art would have been motivated to do so because KOSSIAKOFF teach that multivalency is a hallmark of natural immunoglobulins and is a critical feature to the efficacy of antibodies in vivo and in research, diagnostic, and therapeutic applications (e.g., ¶0223).
Regarding claim 186, reference claims 9-10 in view of KOSSIAKOFF teaches the polypeptide of claim 34 (discussed above). It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the polypeptide to eliminate binding to the protein G variant, as taught by KOSSIAKOFF (see figures 13 and 16; ¶s 0227-0228) to achieve the predictable result of obtaining multispecific protein-G molecules. One of ordinary skill in the art would have been motivated to do so because KOSSIAKOFF teaches these variants provide for exquisite specificity that can be exploited to readily make bi-specific constructions (¶0227, lines 13-16).
Regarding claims 188-191, reference claims 9-10 in view of KOSSIAKOFF teach the polypeptide of claim 34. The reference claims differ from the instant claims by not specifying alternative constructs (knob-in-hole VS linker) or the incorporation of additional antigen binding fragments.
However, KOSSIAKOFF does teach that the Fab domains may be fused through a linker (e.g., see claim 25, pg. 72). As a further alternative, KOSSIAKOFF teaches they may be linked via binding affinity (e.g., knob-in-hole) rather than a linker (¶0228). KOSSIAKOFF also teaches the Fab and G Fab binding domains are conjugated via a linker (¶0228) and may also comprise additional antigen binding fragments (e.g., see figures 14 and 16, ¶0228).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have further modified the reference polypeptide to incorporate these features of the KOSSIAKOFF peptide. One of ordinary skill in the art would have been motivated to do so because KOSSIAKOFF teaches that these fusion proteins will mimic the dimeric antibody structure of the native molecule because there is a flexible linker between the heavy chain Fab region . KOSSIAKOFF also teaches that the composition and length of the linker between the Protein-G variant binding domain and the Fc domain is adjustable, further expanding the utility of these constructs by introducing fusions that contain Protein-G isotypes that can generate multi-specific binding moieties (e.g., ¶0228; see also FIG. 14).
Therefore, claims 34, 36-38 and 186-191 are obvious over claims 1 and 4-12 of U.S. Patent No. 10759834 B2 in view of KOSSIAKOFF et al.
Conclusion
13. No claim is allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES L MCLELLAN whose telephone number is (703)756-1906. The examiner can normally be reached Monday - Thursday 7:30 am - 5:30 pm. *Compressed day off on first Friday of each Bi-week.
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, Misook Yu can be reached at (571) 272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES LYLE MCLELLAN/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641