Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 20 December 2024 has been entered.
Status of Application, Amendments and/or Claims
3. Applicant’s amendments dated 9/20/2024 are considered and entered into record. Claim 4 is amended. Claims 1-8 and 10-11 are pending in the instant application.
4. Claims 1-3 and 6-8 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 21 April 2023.
5. Claims 4-5 and 10-11, drawn to a multimeric molecule that is an antibody, are under examination in the instant application.
Withdrawn Rejections
6. Upon consideration of amendment of claim 4 cancelling “growth factor” and “cytokine”, the rejections of claim 4 and its dependent claims under AIA 35 U.S.C. 103, are withdrawn.
New Rejections
Claim Rejections - 35 USC § 112-Second paragraph
7. 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.
8. 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.
9. Claim 5 is 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.
10. Claim 5 recites that the multimeric molecule of claim 4 is an “antibody”. However, claim 4 recites that the first or second polypeptide is an “antibody Fc-region polypeptide, and the respective other polypeptide domain is selected from the group consisting of a VH domain, a VL domain, a scFv, a scFab, a VH-CH1 pair, a VL-CL pair, a VH-CL pair, a VL-CH1 pair”, all of which are categorized as “antibody fragment” as defined by the instant specification (see page 14, para 3, 4). On the other hand, an “antibody” as defined by the specification (page 14, para 2), is composed of VH and VL regions and constant heavy domains CH1, CH2, CH3. Claim 5 is therefore, unclear and confusing, as to whether it is referring to an antibody or its fragments. Appropriate clarification and correction are required. For present examination, the antibody of claim 5 will be construed as being directed to either an antibody OR antibody fragments.
Claim Rejection - 35 USC § 103
11. 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.
12. Claims 4, 5, 10 and 11 are rejected under AIA 35 U.S.C. 103 as being unpatentable over by Pechan et al Gene Therapy 16: 10-16, 2009 (IDS), and GenBank # AFF59210.1, 2 pages, 3/31/2012, in view of Yang et al, IIH-MSP Principal component Anal of O-linked glycosylation sites in protein sequence, pages 1-6, 2007, and in further view of Petros et al (BBF RFC 44 – Bioscaffold-Linker (1-7; 2009) and Kopetzki et al WO 2015/091130, 6/25/2015 (IDS).
13. The claims are directed to a multimeric molecule comprising at least 2 polypeptides wherein at least one is a linear fusion polypeptide comprising a first polypeptide domain, peptidic linker and second polypeptide domain, wherein the first and second polypeptide domains are linked via a peptidic linker; the peptidic linker is a Gly/Ser linker that lacks a C-terminal serine residue; the second polypeptide domain comprises at the N-terminus an amino acid residue which is not serine, threonine or proline; and the first or second polypeptide domain is an antibody Fc-region polypeptide, and the other polypeptide domain is one from the list recited in claim 4, wherein the linear fusion polypeptide comprises the sequence of SEQ ID NO: 01 (GnSGmX1), wherein X1 is the N-terminal amino acid residue of the second polypeptide; n = 3 or 4 and m = 3 or 4 (claims 4, 11); wherein the linear fusion polypeptide has reduced O-glycosylation compared to a fusion polypeptide having a second polypeptide with serine, threonine or proline at the N-terminus (claim 10). Claim 5 recites that the multimeric molecule is an antibody.
14. Pechan et al teach chimeric polypeptides that are fused (fusion polypeptide), sFLT01 (VEGF binding molecules) consisting of IgG-like domain of soluble receptor Flt-1 (first polypeptide) fused to IgG1 Fc (second polypeptide) or CH3 domain of IgG1 Fc via a polyglycine linker 9Gly. The reference teaches that soluble Flt-1 (sFlt-1) is the extracellular domain of VEGF receptor, and the peptidic linker links (is conjugated to) the C-terminus of the first polypeptide sFlt-1 to the N-terminus of IgG1 heavy chain Fc region (i.e. the first peptide is extracellular domain of VEGF receptor and the second peptide is IgG1 Fc region) (Abstract; Introduction, para 2; Figure 1a; Results, para 1). As the peptidic linker is 9Gly, it inherently lacks the C-terminal serine residue. It is noted that the specification teaches that Gly/Ser peptidic linkers can lack the C-terminal serine residue, or can be a pure glycine linker (page 4, lines 3, 4; page 21, lines 10-13).
15. Pechan et al do not teach that the N-terminus of the second polypeptide (i.e. IgG1 Fc) does not comprise serine, threonine or proline.
16. GenBank # AFF59210.1 teach a human IgG1-Fc region sequence that does not comprise N-terminal threonine, proline or serine residue.
17. Pechan et al or GenBank # AFF59210.1 do not explicitly teach reduced O-glycosylation as recited in claim 10.
18. Yang et al. teach that glycosylation or sugar residue addition to the peptide backbone is the most common post-translational protein modification, and that there is a high abundance of serine, proline and threonine in all positions (including N-terminus) of glycosylated proteins (Introduction, para 1, 2). The reference teaches that proline, serine, threonine and alanine content of O-glycosylated protein is higher than non-glycosylated protein, indicating that the absence of those residues would result in reduced O-glycosylation (instant claim 10). The reference also teaches that serine and threonine near the N-terminus is easily glycosylated (Abstract; Conclusion). Note that Yang et al teach “near” N-terminus, not “at” the N-terminus as recited in instant claims. However, it would be obvious to the person of ordinary skill that “near” N-terminus would also include “at” N-terminus, absent evidence to the contrary. In considering the disclosure of a reference, it is proper to take into account not only specific teaching of the reference but also the inferences which one skilled in the art would be reasonably be expected to draw therefrom (In re Preda, 401 F.2d 825, 159 USPQ 342, 344 (CCPA 1968)). Also, a reference must be considered, under 35 U.S.C. 103, not only for what it expressly teaches but also for what it fairly suggests; all disclosures of prior art, including unpreferred embodiments, must be considered in determining obviousness (In re Burckel 201 USPQ 67 (CCPA 1979)).
19. Pechan et al, GenBank # AFF59210.1 or Yang et al do not teach a multimeric molecule comprising an antibody (claim 5), or the peptidic (G-S-G) linker (claims 4, 11).
20. Petros et al teach that the addition of a glycine-serine-glycine linker between the two coding regions of a protein, results in flexibility and allows the “individual component to fold correctly and independently following translation” (page 2, last para).
21. Pechan et al, GenBank # AFF59210.1, Yang et al or Petros et al do not teach the glycine residues as instantly claimed, or that the multimeric molecule is an antibody.
22. Kopetzki et al teach antibody and fusion polypeptides (multimeric) (page 15, line 1), wherein the linker peptide connecting the parts (polypeptides of the fusion polypeptide) is a Gly/Ser peptide which does not have a terminal serine residue, and wherein the number of glycine residues (‘n’ and ‘m’ of instant claim 4) equals to 3 or 4 (e.g. peptide linker sequences for C8 and C12 constructs in Table on page 17; page 3 lines 15-16) (instant claims 4, 11). The reference teaches a fusion polypeptide comprising antibody or its fragment as the first part (targeting entity) and a biologically active entity as the second part, wherein the biologically active entity includes receptor ligands, enzyme, immunoglobulins, etc. (page 3, lines 20-23; page 6, para 1), and wherein the antibody comprises different antibody structures, such as bispecific antibodies and antibody fragments (page 5, lines 16-25). The reference also teaches that the glycine rich peptide linker can have repetitive units up to 5 residues (i.e., comprises n=4 and m=3 of instant claim 11) (page 11, last para). The reference further exemplifies the making of antibody fusion polypeptides (Examples 2, 3, page 41).
23. It would have been obvious to the person of ordinary skill in the art at the time the invention was made to modify the fusion polypeptide of Pechan et al having IgG1 Fc region as the second polypeptide and polyglycine linker, wherein the IgG1 Fc does not have serine, threonine or proline at the N-terminus resulting in reduced O-glycosylation in view of GenBank # AFF59210.1 and Yang et al, by having a G-S-G peptidic linker and obtaining a multimeric antibody molecule based upon the teachings of Petros et al and Kopetzki et al. The person of ordinary skill in the art would have been motivated to have the IgG1 Fc region N-terminus residues not to contain serine, threonine or proline (as in GenBank # AFF59210.1 sequence), as these residues increase O-glycosylation of proteins and post-translational protein modification (Yang et al), and as O-glycosylation sites result in in a heterogeneous protein product, which is undesirable (Kopetzki et al, page 2, lines 13-18). The person of ordinary skill would also have been motivated to add a glycine-serine-glycine linker between the two coding regions of a protein, as this would provide flexibility and allow the “individual component to fold correctly and independently following translation” (Petros et al). The person of ordinary skill in the art would have further been motivated to obtain an antibody-fusion polypeptides molecule to provide targeted delivery (Kopetzki et al, page 1, lines 12-16). The person of ordinary skill in the art would have had a reasonable expectation of success based on the cumulative disclosures of these prior art references, at the time of filing of the instant invention.
24. Thus, the claimed invention as a whole was prima facie obvious over the combined teachings of the prior art.
Applicant’s Remarks:
25. Applicant states that claim 4 is now amended to delete reference to a growth factor or a cytokine. Applicant asserts that since BMP2 of Qi is not one the recited “other polypeptide domain”, the 103 rejection is rendered moot. Applicant argues that since Crine or Qi do not teach or suggest a polypeptide domain as recited in the currently amended claims, no combination of the cited art can correct the deficiency. Applicant therefore, requests reconsideration and withdrawal of the 103 rejections.
26. Applicant's arguments are fully considered and found to be persuasive. As stated above, based upon consideration of amendment of claim 4, all previously made rejections have been withdrawn, and new rejections have been set forth.
Double Patenting
Non-Statutory
27. 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).
28. 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).
29. 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.
30. 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.
31. Claims 4-5 and 10-11, are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1 and 5-7 of US Patent 10,941,205 in view of Yang et al (2007), Petros et al (2009) and Kopetzki et al (2015).
Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are directed to a fusion polypeptide or an antibody comprising an antibody heavy chain (VH), and a Fab fragment (scFab), wherein the Fab fragment is fused to C-terminus of the heavy chain by a peptide linker, and wherein the N-terminus of the Fab fragment of SEQ ID NO: 3 or SEQ ID NO: 4 does not have serine, threonine or proline.
The only differences between the two sets of claims are:
(i) Instant claims recite the sequence of Gly/Ser peptide linker, while the ‘205 patent claims do not recite a specific linker. However, the use of such linkers would be obvious in view of the teachings of Petros et al and Kopetzki et al for reasons stated above.
(ii) Instant claim 10 recites that the fusion polypeptide has reduced O-glycosylation, while the ‘205 patent claims are silent on this limitation. However, this would be obviously expected of the fused molecule of ‘205 patent as the Fab fragment (second polypeptide) does not have serine, threonine or proline at the N-terminus, which would result in reduced O-glycosylation in view of the teachings of Yang et al.
32. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 10,941,205.
33. Claims 4-5 and 10-11, are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-12 of US Patent 12,227,594 in view of Yang et al (2007) and Petros et al (2009).
Although the conflicting claims are not identical, they are not patentably distinct from each other because in each case the claims are directed to a fusion polypeptide or an antibody comprising an antibody fragment, peptide linker, and IgG1 Fc domain (claims 8-11 of ‘594 patent), wherein: an antibody fragment can be Fv, Fab, scFv, etc. (col 20, lines 19-25 of ‘594 specification); and the second polypeptide can be VL or VH (first VL, first VH, second VL or second VH) (claim 1(a), 1(c) of ‘594 patent) having sequences of SEQ ID NOs: 41, 40, 7 and 8, for example (claim 5(a), 6(a), 7(a) of ‘594 patent), none of which have serine, threonine or proline at the N-terminus.
The only differences between the two sets of claims are:
(i) Instant claims recite the sequence of Gly/Ser peptide linker, while the ‘594 patent claims do not recite a specific linker. However, Gly/Ser linkers are contemplated in the ‘594 patent specification (col 34, lines 35-40). The use of such linkers would be obvious in view of the teachings of Petros et al for reasons stated above.
(ii) Instant claim 10 recites that the fusion polypeptide has reduced O-glycosylation, while the ‘594 patent claims are silent on this limitation. However, this would be obviously expected of the fused molecule of ‘594 patent as the second polypeptide does not have serine, threonine or proline at the N-terminus (as stated above), which would result in reduced O-glycosylation in view of the teachings of Yang et al.
34. Therefore, the instant claims are not patentably distinct over the issued claims in U.S. patent 12,227,594.
Conclusion
35. No claims are allowed.
36. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aditi Dutt whose telephone number is (571)272-9037. The examiner can normally be reached on M-F 9:00am-5:00pm.
37. 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.
38. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Stucker, can be reached on 571-272-0911. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
39. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A. D./
Examiner, Art Unit 1675
20 February 2026
/KIMBERLY BALLARD/Primary Examiner, Art Unit 1675