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 election with traverse of Group I (claims 4, 17, 20, 23, 26-30, 33, 35, 36, 38, 45, 47 and 61) and species of (i) the antibody corresponding to item m) of claim 4 (wherein the VH comprises the HC-CDR1 comprising the amino acid sequence of SEQ ID NO: 121, the HC-CDR2 comprising the amino acid sequence of SEQ ID NO: 122, and the HC-CDR3 comprising the amino acid sequence of SEQ ID NO: 123, and the VL comprises the LC-CDR1 comprising the amino acid sequence of SEQ ID NO: 124, the LC-CDR2 comprising the amino acid sequence of SEQ ID NO: 125, and the LC -CDR3 comprising the amino acid sequence of SEQ ID NO: 126) and (ii) IgG4 Fc in the reply filed on 12/8/2025 is acknowledged. The traversal is on the ground(s) that there would not be a serious burden on the Office to search and examine all of the claims together. This is not found persuasive because the examiner has shown that Groups I-III have separate classification. Separate classification shows that each invention has attained recognition in the art as a separate subject for inventive effort, and also a separate field of search (MPEP 808.02). Therefore, searching the inventions of Groups I-III would impose serious search burden. The requirement is still deemed proper and is therefore made FINAL.
3. Claims 4, 17, 20, 23, 26-30, 33, 35, 36, 38, 45, 47-52 and 61 are pending. Claims 1-3, 5-16, 18-19, 21-22, 24-25, 31-32, 34, 37, 39-44, 46, 53-60 and 62 are canceled. Claims 20, 33, 36 and 48-52 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 12/8/2025.
4. Claims 4, 17, 23, 26-30, 35, 38, 45, 47 and 61 are under examination.
Priority
5. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
6. The information disclosure statement (IDS) submitted on 8/26/2022, 3/26/2024, 6/21/2024 and 2/24/2025 have been considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
7. Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See page 66.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Drawings
8. Figure 1 is objected to because they include the term “Octet”, which is a trade name or a mark used in commerce. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
9. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code, see page 113. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
10. The disclosure is objected to for referring an amino acid sequence with a SEQ ID NO that contains a prohibited sequence, see SEQ ID NO:158 on page 16, 46 and Table 4, for example. Prohibited sequences are those with <10 specifically defined nucleotides or <4 specifically defined amino acids. SEQ ID NOs containing prohibited sequences (skipped sequences) do not have any sequence data in sequence listing. Applicant should amended the specification to replace all relevant SEQ ID NOs with the actual sequences, if originally disclosed. For example, SEQ ID NO:158 does not have any sequence data, and should be replaced with the actual sequence VDY (see page 100).
11. The disclosure is further objected to for use the phrase “fully human monoclonal antibodies” in line 6 of page 105 (line 3 of Example 1). The antibodies generated in the BALB/c mice are not fully human antibodies.
12. The use of the terms Octet, Nanobody, BiTE, which are trade names or a marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Improper Markush Grouping Rejection
13. Claims 4, 23, 26-30, 35, 38, 45, 47 and 61 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
MPEP 2117 states “Claims that set forth a list of alternatives from which a selection is to be made are typically referred to as Markush claims, after the appellant in Ex parte Markush, 1925 Dec. Comm’r Pat. 126, 127 (1924). Although the term “Markush claim” is used throughout the MPEP, any claim that recites alternatively usable members, regardless of format, should be treated as a Markush claim.”.
A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush grouping of the claims is improper because the alternatives defined by the Markush grouping (i.e. antibodies comprising different 6 CDR sequences) are not disclosed in the specification or known in the art to be functionally equivalent and have a common use. Antibodies comprising different 6 CDRs are not functional equivalent because they bind to different epitopes. Antibodies with different CDRs have different sequences, result in different structures, and bind to different epitopes, as such are not functionally equivalent. Antibodies that bind to different epitopes will induce different in vivo responses. Antibodies that bind to a certain epitope of a protein may act as antagonist of that protein, while antibodies that bind to other epitopes of that same protein may act as agonists of that protein, and even further, antibodies that bind to certain other epitopes of that same protein may not induce any effect at all. Zabel et al. (US 2023/0340123A1, pub. date: 10/26/2023) discloses that anti-BTLA antibodies 16-I20A, 15-C19A and 16-H16A augmented SEB-induced IL-2 secretion by T cells, and thus served as BTLA antagonists; anti-BTLA antibodies 12-18A, 8-M23A and 13-F7A suppressed SEB-induced IL-2 secretion by T cells, and thus served as BTLA agonists (Example 5). As such, antibodies that have different VH CDRs and VL CDRs which bind to different epitopes would give rise to different in vivo responses, and may not be regarded as functionally equivalent. Furthermore, they do not share both a substantial structural feature and a common use that flows from the substantial structural feature. While the term “antibody” does impart some structure, the structure that is common to antibodies is generally unrelated to antigen-binding function. The 6 CDRs are generally considered to be the region of contact between the antibody and the antigen.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Objections
14. Claim 45 is objected to for reciting “any one of claim 4”.
15. Claim 30 is objected to for missing a word “is” before “selected from”.
Claim Rejections - 35 USC § 112
16. 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.
17. Claims 26-28 and 30 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.
(i) Regarding claim 26, the phrase “(e.g., a bispecific antibody)“ in line 4 renders the claim indefinite because it is unclear whether the limitation(s) in the parenthesis are part of the claimed invention See MPEP § 2173.05(d).
The reference characters within parenthesis should correspond to the element recited in the claim, , i.e. have same meaning/scope, or refer to same substance. In this case, the reference characters are only examples or preferences to the element recited in the claims.
The phrase “for example” (e.g.) renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
(ii) Claim 26 is indefinite for reciting the phrase “wherein the construct comprises an antibody or antigen-binding fragment thereof selected from the group consisting of…” in lines 2-3. It is unclear “an antibody or an antibody or antigen-binding fragment thereof” in the phare refers to the anti-CD137 antibody moiety mentioned in claim 4 or a different antibody. Because the claim has more than one interpretation, the metes and bounds of the claimed invention cannot be determined and the claim is indefinite.
If applicant intended to refer to the anti-CD137 antibody moiety mentioned in claim 4, the claim should be amended to recite “wherein the anti-CD137 antibody moiety is selected from the group consisting of …”
If applicant intended to refer to a different antibody, the claim should be amended to recite “wherein the construct further comprises a second antibody or antigen-binding fragment thereof selected from the group consisting of …”.
(iii) Claim 27, 28 and 30 are indefinite for the same reasons set forth in part (ii) above for claim 26. To overcome the rejection, claims 27 and 28 can be amended to recite “wherein the anti-CD137 antibody moiety is a humanized anti-CD137 full length antibody”, and “wherein the anti-CD137 antibody moiety is a humanized anti-CD137 single chain Fv”, respectively; claim 30 can be amended to recite “wherein the anti-CD137 antibody moiety comprising a Fc …”.
Claim Rejections - 35 USC § 112
18. 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.
19. Claim 26 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.
For this rejection, the limitation “an antibody or an antibody or antigen-binding fragment thereof” in lines 2-3 is interpreted as the anti-CD137 antibody moiety mentioned in claim 4.
Claim 26 depends from claim 4. Claim 4 requires the anti-CD137 antibody moiety to comprise 6 CDRs. Claim 26 recites “VHH”, which comprises only 3 CDRs. Therefore, claim 26 does not further limit claim 4.
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.
Double Patenting
20. 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.
21. Claims 4, 17, 23, 26-30, 35, 38, 45, 47 and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,18, 21, 24, 27, 30, 47, 50-54, 60, 64-66, 68-69, 84, 86-91 and 102 of copending Application No. 17/822,737 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1,18, 21, 24, 27, 30, 47, 50-54, 60, 64-66, 68-69, 84, 86-91 and 102 of the copending Application No. 17/822,737 (reference application) disclose a multispecific antibody that binds to human CD137 and human EGFR, comprising a first antibody moiety that binds to human CD137 and a second antibody moiety that binds to human EGFR, wherein the first antibody moiety comprises a heavy chain variable region (VH) comprising amino acids having the sequence set forth in SEQ ID NO: 127 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 128, wherein the first antibody moiety is a human CD137 agonist antibody, wherein the first antibody moiety comprises an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a multispecific antibody a scFv, a Fab fragment, a Fab' fragment, a F(ab')2, and a scFv-Fc fusion, the Fc region comprises an IgG4 Fc region, and the IgG4 Fc region comprises a S228P mutation. The claims further disclose an immunoconjugate comprising the multispecific antibody, linked to a therapeutic agent or a label, a pharmaceutical composition comprising the multispecific antibody, and a pharmaceutically acceptable carrier, and a kit comprising the multispecific antibody. The amino acid sequences of SEQ ID NOs: 127 and 128 are 100% identical to instant SEQ ID NOs: 127 and 128, respectively (see sequence alignments below). SEQ ID NO: 127 comprises instant SEQ ID NOs: 121-123. SEQ ID NO: 128 comprises instant SEQ ID NO: 124-126.
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22. Claims 4, 17, 23, 26-30, 35, 38, 45, 47 and 61 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4, 18, 21, 24, 27, 30, 49-54, 57, 59-61, 63-64, 76-82 and 94 of copending Application No. 17/822,750 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 4, 18, 21, 24, 27, 30, 49-54, 57, 59-61, 63-64, 76-82 and 94 of copending Application No. 17/822,750 (reference application) disclose a multispecific antibody that binds to CD137 and HER2, comprising a first antibody moiety that binds to CD137 and a second antibody moiety that binds to HER2, wherein the first antibody moiety comprises a heavy chain variable region (VH) comprising amino acids having the sequence set forth in SEQ ID NO: 127 and a light chain variable region comprising amino acids having the sequence set forth in SEQ ID NO: 128, wherein the first antibody moiety is a human CD137 agonist antibody, wherein the first antibody moiety comprises an antibody or antigen-binding fragment thereof selected from the group consisting of a full-length antibody, a multispecific antibody a scFv, a Fab fragment, a Fab' fragment, a F(ab')2, and a scFv-Fc fusion, the Fc region comprises an IgG4 Fc region, and the IgG4 Fc region comprises a S228P mutation. The claims further disclose an immunoconjugate comprising the multispecific antibody, linked to a therapeutic agent or a label, a pharmaceutical composition comprising the multispecific antibody, and a pharmaceutically acceptable carrier, and a kit comprising the multispecific antibody. The amino acid sequences of SEQ ID NOs: 127 and 128 are 100% identical to instant SEQ ID NOs: 127 and 128, respectively (see sequence alignments below). SEQ ID NO: 127 comprises instant SEQ ID NOs: 121-123. SEQ ID NO: 128 comprises instant SEQ ID NO: 124-126.
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Conclusion
23. No claims are allowed.
24. Any inquiry concerning this communication or earlier communications from the examiner should be directed to HONG SANG whose telephone number is (571)272-8145. The examiner can normally be reached Monday-Friday 8am-5pm.
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, Janet Epps-Smith can be reached at 5712720757. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HONG SANG/Primary Examiner, Art Unit 1646